HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fichna, J. Articles by Do Rego, J.-C. Search for Related Content PubMed Articles by Fichna, J. Articles by Do Rego, J.-C.

The Endomorphin System and Its Evolving Neurophysiological Role

Laboratory of Experimental Neuropsychopharmacology, Centre National de la Recherche Scientifique-Formation de Recherche en Evolution 2735, European Institute of Peptide Research (Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23), Faculty of Medicine and Pharmacy, Institute of Biomedical Research, University of Rouen, Rouen, France (J.F., J.C., J.-C.d.R.); and Laboratory of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland (J.F., A.J.)

Abstract

I. Introduction

II. Structure-Activity Relationship Studies

III. Distribution

IV. Receptors

V. Enzymatic Degradation

VI. Neurophysiological Role

A. Biological Effects of Endomorphins

1. Pain.

a. Central administration of endomorphins.

b. Peripheral administration of endomorphins.

2. Tolerance.

3. Physical Dependence.

4. Effects on Locomotor Activity.

5. Behavioral Sensitization.

6. Drug Addiction, Mechanism of Reward.

7. Psychiatric disorders.

a. Stress.

b. Anxiety.

c. Depression and other psychiatric disorders.

8. Social Defeat.

9. Food Intake.

10. Sexual Behavior.

11. Learning and Memory.

12. Effects on Cardiovascular System.

13. Effects on Respiratory System.

14. Effects on Gastrointestinal Tract.

B. Endomorphins, Neurotransmitters, and Neurohormones

1. Modulation of Dopamine Transmission.

2. Modulation of Noradrenaline Transmission.

3. Modulation of Serotonin Transmission.

4. Modulation of Acetylcholine Transmission.

5. Modulation of Neurohormone Release.

VII. Conclusions

	Abstract

Top Next

	I. Introduction

Top Previous Next

 
The three opioid receptors, designated µ, , and , which were found in the central and peripheral nervous systems, mediate the biological functions of opioids. After the discovery of -opioid receptor-selective enkephalins in 1975 (Hughes et al., 1975), other peptides have been characterized as endogenous ligands for the opioid receptors (Table 1) (Goldstein et al., 1979; Nakanishi et al., 1979; Bloom, 1983). Naturally occurring opioid peptides, which were shown to bind preferentially to the µ-opioid receptor, were β-casomorphin (Tyr-Pro-Phe-Pro-Gly-Pro-Ile) from the tryptic digests of β-casein (Henschen et al., 1979), hemorphin-4 (Tyr-Pro-Trp-Thr) from digests of hemoglobin (Brantl et al., 1986), Tyr-Pro-Leu-Gly-NH₂ (Tyr-MIF-1¹) and Tyr-Pro-Trp-Gly-NH₂ (Tyr-W-MIF-1), both isolated from the brain (Horvath and Kastin, 1989; Erchegyi et al., 1992). However, until 1997, no mammalian peptide was identified that would show substantial µ-opioid receptor affinity and selectivity.

In 1997, Zadina's group (Zadina et al., 1997) synthesized a number of Tyr-W-MIF-1 analogs, containing all possible natural amino acid substitutions at position 4, which were subsequently screened for the opioid receptor binding. A biologically potent sequence, Tyr-Pro-Trp-Phe-NH₂, was discovered and then identified in the bovine brain (Zadina et al., 1997) and human cortex (Hackler et al., 1997). This new peptide, which was named endomorphin-1, showed remarkable affinity for the µ-opioid receptor (360 pM) and selectivity of 4000- and 15,000-fold for the µ-opioid receptor over the - and -opioid receptors, respectively. Endomorphin-1 was extremely potent in the guinea pig ileum assay, a classic test for µ-opioid receptor agonist activity (Zadina et al., 1997). This peptide also had a potent and specific antinociceptive effect in vivo, as shown in the tail-flick test (Hackler et al., 1997; Zadina et al., 1997). A second peptide, endomorphin-2 (Tyr-Pro-Phe-Phe-NH₂), which differs by one amino acid from endomorphin-1, was also isolated. Endomorphin-2 was shown to be almost as potent as endomorphin-1 (Hackler et al., 1997; Zadina et al., 1997). Endomorphins were the first peptides isolated from brain that bind to the µ-opioid receptor with high affinity and selectivity and therefore were proposed as endogenous µ-opioid receptor ligands. However, their precursor(s) still remain(s) unidentified.

In this review we discuss the biological effects of endomorphin-1 and endomorphin-2 in relation to their distribution in the central and peripheral nervous systems. We describe the relationship between these µ-opioid receptor-selective peptides and endogenous neurohormones and neurotransmitters. We evaluate the role of endomorphins from the physiological point of view and report selectively on the most important findings in their pharmacology, rather than present all available data.

	II. Structure-Activity Relationship Studies

Top Previous Next

 
Full descriptions of all the structure-activity relationships studies of endomorphins are beyond the scope of this review. For more data on endomorphin analogs, please refer to the articles by Janecka et al. (2004), Gentilucci and Tolomelli (2004), and Janecka and Kruszynski (2005).

The structures of endomorphin-1 and endomorphin-2 are quite distinct from those of the traditional opioid peptides (endorphins, enkephalins, and dynorphins), which all share the Tyr-Gly-Gly-Phe sequence at the N terminus. The N-terminal message sequence of endomorphin-1 is composed of two pharmacophoric amino acid residues, Tyr and Trp (in endomorphin-2 Trp is replaced by Phe), in which the amino and phenolic groups of Tyr and the aromatic ring of Trp (or Phe) are required for µ-opioid receptor recognition. The sequence of endomorphins also includes a spacer (Pro), which joins the pharmacophoric residues. Podlogar et al. (1998) presented a structural and comparative study of endomorphin-1 to identify its bioactive conformation and attributes responsible for the µ-opioid receptor selectivity. Nuclear magnetic resonance data showed that Pro² provides the necessary stereochemical requirements for activity of endomorphin-1 at the µ-opioid receptor. The bioactive conformation of endomorphin-1 is characterized by a structure, in which the Tyr¹ and Trp³ side chains have opposite orientations with respect to Pro² (Paterlini et al., 2000). Synthesizing pseudoproline-containing analogs of endomorphin-2, which are known to be quantitative inducers of the cis conformation, the group of Schiller (Keller et al., 2001) demonstrated that the Tyr-Pro amide bond in the bioactive conformation is cis.

	III. Distribution

Top Previous Next

 
Radioimmunological and immunocytochemical analyses revealed that endomorphin immunoreactivities (IRs) are distributed throughout the human, bovine, and rodent central nervous systems (CNS) (Hackler et al., 1997; Martin-Schild et al., 1997, 1999; Pierce et al., 1998; Schreff et al., 1998; Pierce and Wessendorf, 2000). Both endomorphins are abundant in the areas such as the stria terminalis, the periaqueductal gray (PAG), the locus coeruleus (LC), the parabrachial nucleus, and the nucleus of the solitary tract (NTS) (Table 2). However, there are also important differences in the neuroanatomical localization of these peptides. Endomorphin-1 is widely and densely distributed throughout the brain and upper brainstem and is particularly abundant in the nucleus accumbens (Nac), the cortex, the amygdala, the thalamus, the hypothalamus, the striatum, and the dorsal root ganglia (Schreff et al., 1998; Martin-Schild et al., 1999). In contrast, endomorphin-2 is more prevalent in the spinal cord and lower brainstem (Martin-Schild et al., 1999; Pierce and Wessendorf, 2000); endomorphin-2-immunoreactive cell bodies were most prominent in the hypothalamus and the NTS, whereas endomorphin-2-immunoreactive varicose fibers were mainly observed in the substantia gelatinosa of the medulla and the spinal cord dorsal horn. More modest endomorphin-2 IR was seen in the Nac, substantia nigra, nucleus raphe magnus, ventral tegmental area (VTA), and pontine nuclei and amygdala. The differences in the distribution of endomorphins could indicate the existence of two distinct endomorphin precursors or two different processing pathways of the same precursor.

View this table: [in this window] [in a new window]   TABLE 2 Distribution of endomorphins in the selected structures of the central nervous system Data from Martin-Schild et al. (1997, 1998, 1999), Schreff et al. (1998), Barr and Zadina (1999), Pierce et al. (1998), and Pierce and Wessendorf (2000).

The distribution of endomorphin IRs in the CNS seems to be similar to that of the classic endogenous opioid peptides (Hokfelt et al., 1977; Simantov et al., 1977; Johansson et al., 1978; Sar et al., 1978; Uhl et al., 1979). However, in the case of endomorphin-2 two major differences were found. Unlike -opioid receptor-selective enkephalin (Watson et al., 1977; Sar et al., 1978) and -opioid receptor-selective dynorphin (Gramsch et al., 1982), endomorphin-2 IR was sparse in the hippocampus and striatum (Schreff et al., 1998; Martin-Schild et al., 1999). In this way the distribution of endomorphin-2 was analogous to that of β-endorphin, an endogenous µ-opioid receptor-selective ligand (Finley et al., 1981).

The reports on the presence of endomorphins outside the CNS are scarce. Jessop et al. (2000) used a combination of specific radioimmunological assays and reversed phase high-performance liquid chromatography techniques to characterize the level of endomorphin IR in rat and human peripheral tissue samples. They found that endomorphin-1 IR and endomorphin-2 IR are present in significant amounts in human spleen; relatively high levels of endomorphin IR were also detected in the rat spleen, thymus, and blood. Because very low amounts of endomorphin IR were found in anterior and posterior rat pituitaries, secretion from these glands could not account for the significant plasma level of endomorphins. The authors of that report suggested that endomorphins are secreted into the general circulation from the nerve fibers and terminals of the spinal cord. Interestingly, in the same study a number of peaks of endomorphin-1 IR and endomorphin-2 IR, which do not coelute with their respective synthetic standards, were also detected. These might represent precursor polypeptides or degradation products of endomorphin-1 and endomorphin-2, or their post-translational modifications.

Endomorphins were also detected in immune cells in inflamed subcutaneous tissue, whereas they were almost absent in noninflamed tissue (Mousa et al., 2002). The endomorphin-positive cells could only be identified in the periphery of inflammatory foci and had morphological appearances consistent with macrophages/monocytes, lymphocytes, and polymorphonuclear leukocytes.

	IV. Receptors

Top Previous Next

 
The µ-opioid receptors belong to the superfamily of heterotrimeric, guanine-nucleotide binding, G-protein-coupled receptors. The results of numerous in vitro studies clearly demonstrated that the µ-opioid receptors are exclusive binding sites for endomorphins. In the classic binding assays on the rat and mouse brain membrane preparations, both peptides displaced naloxone, Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO), and other µ-opioid receptor-selective ligands in a concentration-dependent manner (for review, see Horvath, 2000). Endomorphins stimulated [³⁵S]guanosine 5'-O-(3-thio)triphosphate binding through the µ-opioid receptors in rat thalamus membrane preparations (Kakizawa et al., 1998; Sim et al., 1998; Fichna et al., 2006a), in the PAG (Narita et al., 2000), and in the pons/medulla of µ-opioid receptor-nondeficient mice (Mizoguchi et al., 2000). Both peptides were potent µ-opioid receptor agonists in the aequorin luminescence-based calcium assay performed on recombinant Chinese hamster ovary cell lines (Fichna et al., 2006b). The autoradiographic methods showed that in the CNS endomorphins labeled the same binding sites as DAMGO, a classic µ-opioid receptor-selective ligand (Goldberg et al., 1998; Kakizawa et al., 1998; Sim et al., 1998). Results of the in vivo studies also demonstrated that endomorphins are µ-opioid receptor ligands. The intracerebroventricular (i.c.v.) administration of endomorphins produced a potent antinociceptive effect in wild-type mice (for review, see Horvath, 2000) and no significant effect in µ-opioid receptor knockout mice (for reviews, see Sakurada et al., 2002; Narita et al., 1999; Zadina et al., 1999; Tseng, 2002). Intrathecal (i.t.) administration produced significant antinociception in the tail-flick, paw-withdrawal, tail pressure, and flexor-reflex tests in adult rodents (Stone et al., 1997; Zadina et al., 1997; Goldberg et al., 1998; Horvath et al., 1999; Sakurada et al., 1999, 2000, 2001; Ohsawa et al., 2001; Grass et al., 2002).

Endomorphin-1 and endomorphin-2 are regarded as partial agonists of µ-opioid receptors. The efficacy of endomorphins in many bioassays, such as guanosine 5'-O-(3-thio)triphosphate binding, is slightly lower than that of DAMGO but higher than that of morphine (Alt et al., 1998; Harrison et al., 1998; Sim et al., 1998). The extent to which these relative efficacies apply to the biological activity of endomorphins has yet to be elucidated.

The endomorphins are principal, but not exclusive, endogenous ligands of µ-opioid receptors. In the CNS, endomorphins, although anatomically positioned to activate the µ-opioid receptors, are not selectively associated with the regions expressing these binding sites. In several telencephalic and limbic structures, µ-opioid receptors and endomorphin-immunoreactive fibers are colocalized. These include septal nuclei, the bed nucleus of the stria terminalis, Nac, the amygdaloid complex, and many hypothalamic nuclei (for reviews, see Zadina et al., 1999, Zadina, 2002; Martin-Schild et al., 1999). There are also brain regions that contain low concentrations of endomorphins, in which significant numbers of µ-opioid receptors can be found, namely the amygdala (telencephalon), the thalamus, the hypothalamus (diencephalon), and the PAG (mesencephalon). Of note is the negligible amount of endomorphin IR in the striatum, a region known to express high levels of µ-opioid receptors (Pierce and Wessendorf, 2000). µ-Opioid receptors have also been detected outside the CNS, in the enteric nervous system (for review, see Olson et al., 1998) and throughout the immune tissues (Sharp et al., 1998), where they were found to be colocalized with endomorphins (Jessop et al., 2000).

Recent studies indicated that endomorphin-1 and endomorphin-2 produce their biological effects by stimulating functionally diverse subtypes of µ-opioid receptors, µ₁ and µ₂, which might be responsible for their distinct pharmacological activity (Sakurada et al., 1999, 2000; Tseng et al., 2000). The µ₁-opioid receptor antagonist naloxonazine was shown to block the antinociception induced by i.c.v. administration of endomorphin-2 more effectively than endomorphin-1, whereas β-funaltrexamine inhibited both. Spinal pretreatment with antisense oligodeoxynucleotides against different exons in the µ-opioid receptor gene differentially attenuated the antinociception induced by endomorphin-1 and endomorphin-2 (Wu et al., 2002; Garzon et al., 2004). These results showed that µ₂-opioid receptors would be stimulated by both endomorphin-1 and endomorphin-2, whereas µ₁-opioid receptors would be stimulated only by endomorphin-2. Further studies revealed that µ₁-opioid receptors mediate supraspinal analgesia and modulate acetylcholine (ACh) and prolactin release, whereas µ₂-opioid receptors mediate spinal analgesia, respiratory depression, and inhibition of gastrointestinal transit (Pasternak, 1993).

	V. Enzymatic Degradation

Top Previous Next

 
The majority of opioid peptides undergo rapid enzymatic degradation (Egleton et al., 1998). Most of the extracellular peptide-degrading enzymes are membrane-bound exo- and endopeptidases, integral membrane proteins that have active sites facing the extracellular space. An intracellular cleavage of opioid peptides by cytosolic peptidases is also possible.

Endomorphins seem to be vulnerable to enzymatic cleavage, and several enzymes have been proposed as participants in endomorphin degradation (Tomboly et al., 2002) (Fig. 1). Aminopeptidase M (EC 3.4.11.2) and aminopeptidase P (EC 3.4.11.9) could degrade N-terminal Tyr-Pro peptide bonds, release an N-terminal amino acid, and generate tripeptides from endomorphins (Dua et al., 1985; Harbeck and Mentlein, 1991). The literature data also indicate that, when the N-terminal hydrophobic residue is followed by a Pro residue, the two amino acids may be released by aminopeptidase M as an intact dipeptide (Bairoch, 1996). Carboxypeptidase Y (serine peptidase, EC 3.4.16.5) and proteinase A (nonpepsin-type acid endopeptidase, EC 3.4.23.6) in the first step could convert the C-terminal amide group into a carboxyl group and then catalyze the hydrolysis of the Xaa³–Phe⁴ peptide bond, where Xaa indicates a natural amino acid) (Berne et al., 1990; Peter et al., 1999). Dipeptidyl-peptidase IV (DPP IV) (EC.3.4.14.5), a membrane-bound serine proteinase, removes dipeptides from the amino terminus of peptides containing proline as the penultimate amino acid and has also been proposed to participate in endomorphin degradation (Kato et al., 1978).

View larger version (19K): [in this window] [in a new window]   FIG. 1. Enzymatic degradation pathways of endomorphin-1 and endomorphin-2.

Interestingly, some authors claim that endomorphin-1 is more resistant to enzymatic degradation in vivo than endomorphin-2 (Fujita and Kumamoto, 2006). This is in good agreement with the observation that the duration of spinal antinociceptive effects was significantly longer for endomorphin-1 than for endomorphin-2 (Grass et al., 2002) and that endomorphin-1 required a longer pretreatment time than endomorphin-2 before tolerance was observed (Stone et al., 1997). This might also explain a relatively shorter duration of the antidepressant-like activity of i.c.v. administered endomorphin-2 in mice (Fichna et al., 2007).

One reason the elucidation of the degradation pathways of endomorphins was necessary was to isolate their effects from these produced by the degradation products. Because of structural similarities to the parent compound, the degradation products might compete with endomorphins for the receptor binding site and could influence their biological activity. However, Szatmari et al. (2001) demonstrated that the primary degradation products of endomorphin-1, Tyr-Pro-Trp-Phe-OH and Pro-Trp-Phe-OH, possess low µ-opioid receptor binding affinity, do not activate G-proteins and have no antinociceptive activity.

The effect of peptidase inhibitors on endomorphin degradation has also been studied. Spetea et al. (1998) examined the influence of peptidase inhibitors on the binding characteristics of [³H]endomorphin-2 in rat brain membrane preparations and showed that in the absence of peptidase inhibitors 40% of the radioligand in the incubation mixture was destroyed. Actinonin, but not thiorphan, was found to be effective in inhibiting the degradation of endomorphin-1 in a 6-day-old rat spinal cord homogenate (Sugimoto-Watanabe et al., 1999). Endomorphin-2-induced antinociception was remarkably enhanced in the paw withdrawal test when diprotin A (Ile-Pro-Ile), a DPP IV inhibitor, was simultaneously injected (Sakurada et al., 2003): the peptide in combination with diprotin A was 5-fold more potent than endomorphin-2 alone in producing antinociceptive effects. Shane et al. (1999) reported that i.c.v. administered Ala-pyrrolidonyl-2-nitrile, another specific inhibitor of DPP IV, increased the magnitude, duration, and potency of endomorphin-2-induced antinociception in the rat tail-flick test.

	VI. Neurophysiological Role

Top Previous Next

 
A. Biological Effects of Endomorphins

The neuroanatomical distribution of endomorphins and the µ-opioid receptors in the CNS reflects their potential endogenous role in many major biological processes. These include perception of pain, responses related to stress, and complex functions such as reward, arousal, and vigilance, as well as autonomic, cognitive, neuroendocrine, and limbic homeostasis (Fig. 2). Some of these phenomena, summarized in Tables 3 and 4, will be discussed in the following sections.

View larger version (32K): [in this window] [in a new window]   FIG. 2. Major structures in the central nervous system implicated in endomorphin-dependent effects. ARC, arcuate nucleus; DMH, dorsomedial nucleus; DTN, dorsal nucleus; HPT, hypothalamus; LC, locus coeruleus; LH, lateral nucleus; NTS, nucleus of the solitary tract (cv, caudal ventrolateral; im, intermediate, ro, rostral); PAG, periaqueductal gray; PBN, parabrachial nucleus; PVN, paraventricular nucleus; RD, caudal dorsomedial part of NTS; VMH, ventromedial nucleus

1. Pain. An important role of endomorphins in pain modulation is indicated by their presence in well-characterized nociceptive pathways (Fields and Basbaum, 1994; Guilbaud et al., 1994): endomorphin-containing neuronal elements were found in most regions of the spino(trigemino)-ponto-amygdaloid pathway (Fig. 3). These regions, which include the caudal nucleus of spinal trigeminal tract, parabrachial nucleus, NTS, PAG, nucleus ambiguous, LC, and midline thalamic nuclei, are known to be involved in the transmission of the nociceptive information by direct input from the primary afferents and/or as relay nuclei to other pain-processing circuits (for reviews, see Fields and Basbaum, 1978; Basbaum and Fields, 1984; Przewlocki et al., 1999; Przewlocki and Przewlocka, 2001). Endomorphins were also found in amygdala, which has been proposed to play an important role in nociception (Manning and Mayer, 1995), particularly with regard to the affective influences on and responses to noxious events (Bernard et al., 1992; Helmstetter and Bellgowan, 1993; Watkins et al., 1993).

View larger version (24K): [in this window] [in a new window]   FIG. 3. Neuroanatomical distribution of endomorphin-1 (EM-1) and endomorphin-2 (EM-2) in major structures involved in the sensation, transmission, and modulation of pain. ++, dense endomorphin-like immunoreactivity; +, moderate endomorphin-like immunoreactivity; -, no endomorphin-like immunoreactivity observed. Arrows represent major ascending and descending pain pathways. Adapted from Kanjhan (1995) with permission from Blackwell Publishing.

Zadina (2002) suggested that endogenous endomorphin-2, due to its specific neuroanatomical localization, might be involved in the earliest stages of nociceptive information processing. To begin with, endomorphin-2 IR was found to be predominantly present in the spinal cord, in the superficial layers of the dorsal horn, and in the primary afferent fibers (including small diameter primary afferent neurons, i.e., most likely nociceptors), whose cell bodies are localized within the dorsal root ganglia (Mousa et al., 2002). These are the regions with the highest densities of µ-receptors in the nervous system (Martin-Schild et al., 1997) and are thought to play an important role in the modulation of nociceptive transmission by various endogenous substances, including opioids (for review, see Fürst, 1999). Moreover, the electrical stimulation of the dorsal roots was shown to promote the release of endomorphin-2 from dense-cored vesicles, situated in dorsal horn axons (Williams et al., 1999; Wang et al., 2002). Thus, it was hypothesized that endomorphin-2 could serve both a regulatory function, by hyperpolarizing the membranes on intrinsic neurons of the dorsal horn and decreasing the excitability of postsynaptic µ-opioid receptors (Wu et al., 1999), and an autoregulatory function, by limiting the release of excitatory transmitters, glutamate (Glu), substance P, -aminobutyric acid, glycine, and calcitonin gene-related peptide through the activation of presynaptic µ-opioid autoreceptors on primary afferent fibers in the spinal cord (Yajiri and Huang, 2000; Wu et al., 2003) (Fig. 4). Endomorphin-2 might also modify pain sensations from the visceral organs and alter the efferent components of the autonomic nervous system by interacting with their preganglionic neurons (Martin-Schild et al., 1997). This latter hypothesis was recently confirmed by Silverman et al. (2005).

View larger version (28K): [in this window] [in a new window]   FIG. 4. Hypothetical involvement of endogenous endomorphin-2 (EM-2) in the earliest stage of pain sensation, transmission, and modulation. 1, regulatory function. Decrease of excitability of postsynaptic µ-opioid receptors. 2, autoregulatory function. Inhibition of the release of excitatory transmitters [calcitonin gene-related peptide (CGRP), glutamate (Glu), substance P (SP)]. DYN A, dynorphin A.

View larger version (31K): [in this window] [in a new window]   FIG. 5. Simplified representation of pain modulatory pathways activated by supraspinally and spinally administered endomorphin-1 and endomorphin-2. DYN A, dynorphin A; MET-ENK, Met-enkephalin. Adapted from Tseng (2002).

Hung et al. (2003) determined the effects of i.t. pretreatment with 6-OHDA and 5,7-DHT to deplete NA and 5-HT, respectively, on the antinociception induced by supraspinally administered endomorphins. They found that 3-day i.t. pretreatment with 6-OHDA, which depleted spinal NA (>90%), completely abolished the antinociception induced by i.c.v. administration of endomorphins. These results strongly indicate that the release of NA in the spinal cord plays an essential role in the endomorphin-induced antinociception. The 3-day i.t. pretreatment with 5,7-DHT, which depleted both 5-HT (>90%) and NA (up to 25%) attenuated, but did not block, the endomorphin-induced antinociception. These data demonstrate that the adrenergic pathway is more important than the serotonergic pathway in mediating the antinociception activated by supraspinally administered endomorphins.

In the same study the antinociception induced by spinally administered endomorphins was blocked by i.t. pretreatment with the µ-receptor antagonists, but not with 6-OHDA or 5,7-DHT (Ohsawa et al., 2001; Hung et al., 2003). These observations clearly indicated that direct stimulation of the µ-opioid receptors, located in the dorsal horn of the spinal cord, mediates the antinociception induced by spinally administered endomorphins, without the involvement of NA or 5-HT transmission.

Supraspinal endomorphin-2- but not endomorphin-1-induced tail-flick inhibition was blocked by i.c.v. or i.t. pretreatment with an antiserum against dynorphin A(1-17) or norbinaltorphimine. Similarly, it was blocked by i.t. pretreatment with an antiserum against Met-enkephalin or naltriben (Tseng et al., 2000). These findings indicated that the supraspinal endomorphin-2-induced antinociception also involved additional components, corresponding to the release of dynorphin A(1-17), as well as Met-enkephalin, acting on the - and ₂-opioid receptors, respectively. This accounts for the differences in the antinociceptive effects between endomorphin-1 and endomorphin-2 (Fig. 4).

b. Peripheral administration of endomorphins. Several studies have shown that peripherally administered opioids produce analgesic effects mediated through peripheral µ- and -opioid receptors located on primary afferent neurons (Craft et al., 1995; Kolesnikov and Pasternak, 1999; Nozaki-Taguchi and Yaksh, 1999). However, detailed pathways and exact mechanisms, through which peripherally administered opioids produce antinociception, have not been elucidated.

As for endomorphins, there is only one report on their analgesic effect after peripheral administration. Li et al. (2001) used various nociceptive tests to demonstrate that endomorphin-1 produced a dose-dependent, naloxone-reversible analgesia after i.p. administration in rats. The peak analgesic effect appeared later in the time course and was less pronounced than that induced by centrally (i.c.v. and i.t.) administered peptide. Because it is generally believed that peripherally administered endomorphins, because of their rapid enzymatic degradation in peripheral tissues and low permeation through the brain-blood barrier, cannot reach the CNS in an amount sufficient to elicit analgesia (Hau et al., 2002; Spampinato et al., 2003), these observations need to be further investigated. The question whether the analgesic effect resulting from this route of administration has a peripheral or a central origin needs to be answered as well.

2. Tolerance. The development of tolerance, as well as physical dependence limits the clinical use of the opioids as pharmacological agents. Numerous studies have shown that the µ-opioid receptor ligands are responsible for the emergence of both phenomena (Schiller et al., 1999; Shen et al., 2000; Spreekmeester and Rochford, 2000). Recently, much emphasis has been put on the µ-opioid receptor-mediated intracellular signal transduction mechanisms and long-lasting molecular and cellular adaptations after chronic treatment with the µ-opioid receptor ligands (Defer et al., 2000; Heyne et al., 2000; Law et al., 2000). The ability of endomorphins, being potent µ-opioid receptor-selective agonists, to develop tolerance and dependence has also been investigated.

As it was shown in the in vitro assays, acute treatment with or chronic administration of endomorphins may stimulate the development of tolerance (Higashida et al., 1998; McConalogue et al., 1999). Nevo et al. (2000) demonstrated that forskolin-stimulated adenylyl cyclase activity was elevated above control levels after naloxone in µ-opioid receptor-expressing Chinese hamster ovary cells chronically treated with endomorphin-1 and endomorphin-2. Similarly, chronic exposure to endomorphins stimulated adenylyl cyclase activity in µ-opioid receptor-expressing African green monkey kidney cells cotransfected with type I and V isozymes (Nevo et al., 2000).

In vivo investigations also showed that pretreatment with endomorphins may develop tolerance. First, it was demonstrated that i.t. pretreatment with endomorphin-1 and endomorphin-2 attenuated the antinociceptive response in mice induced by i.t. administration of endomorphin-1 and endomorphin-2, respectively, and developed acute tolerance to endomorphins (Stone et al., 1997; Higashida et al., 1998; Horvath et al., 1999). Further studies showed that i.c.v. or i.t. administration in mice and rats of a single high dose of endomorphin-1 or endomorphin-2 induced an acute antinociceptive tolerance to the subsequent challenging dose of i.c.v. or i.t. administered endomorphin-1 or endomorphin-2, respectively (Wu et al., 2001, 2003; Hung et al., 2002; Labuz et al., 2002). Interestingly, endomorphins induced the development of tolerance much faster than morphine, although endomorphin-1 required a longer pretreatment time than endomorphin-2 before the acute antinociceptive tolerance was observed. It was proposed that these diverse effects might result from different peptide half-lives or differences in the µ-opioid receptor selectivity or divergent neuronal mechanisms and not from the degree of receptor stimulation by endomorphins or differences in the opioid receptor desensitization (Wu et al., 2001).

Labuz et al. (2002) reported on results obtained in a cross-tolerance study, in which the antinociceptive effects of endomorphins and morphine were compared in tail-flick and paw pressure tests in rats. The animals made tolerant to endomorphin-2 exhibited a partial antinociceptive cross-tolerance to endomorphin-1, whereas rats tolerant to endomorphin-1 showed no cross-tolerance to endomorphin-2. The study also described the cross-tolerance between morphine and endomorphin-1, suggesting a common target, which was probably the µ₂-opioid receptor subtype. Because no cross-tolerance was observed between morphine and endomorphin-2, it was suggested that endomorphin-2 acts via another µ-opioid receptor subtype, apparently µ₁, which could also be a different splice variant or a physical state of the µ-opioid receptor.

As discussed above, so far only animal models of pain have been used to characterize the influence of endomorphins on the development of tolerance. However, tolerance to other endomorphin effects needs to be elucidated. This study might be particularly interesting, as tolerance did not develop to all of the effects of morphine: for example, it did not occur to morphine-induced locomotor activity, which is linked to the physical dependence (Spanagel et al., 1998).

3. Physical Dependence. Chronic administration of opioids usually results in physical dependence, as measured in terms of the appearance of withdrawal symptoms after cessation of the drug or when an opioid antagonist is administered. In animals, the opioid withdrawal symptoms include abnormal posture (Pineda et al., 1998), diarrhea (Miranda and Pinardi, 1998; Pineda et al., 1998), hypothermia (Thornton and Smith, 1998), changes in blood pressure (Zhang and Buccafusco, 1998), and several others (for reviews, see Vaccarino et al., 1999; Vaccarino and Kastin, 2000, 2001). In some cases single, but not chronic, administration of opioids is necessary for the development of dependence (Kest et al., 1998). The µ-opioid receptor ligands are regarded as being mainly responsible for the development of physical dependence and drug addiction (Reisine and Pasternak, 1996; Rockhold et al., 2000).

McConalogue et al. (1999) demonstrated that endomorphins specifically activated the µ-opioid receptor and induced its endocytosis in cells transfected with the µ-opioid receptor cDNA, as well as in the enteric neurons that naturally express the µ-opioid binding sites. Endomorphin-induced endocytosis and trafficking of the µ-opioid receptor may mediate receptor desensitization, resensitization and down-regulation, mechanisms that regulate cellular responsiveness to ligand stimulation and that might be important in the development of opioid tolerance and addiction (Bohm et al., 1997).

To examine the possible effects of endomorphins on physical dependence in vivo, Chen et al. (2003) investigated the ability of both peptides to induce naloxone-precipitated withdrawal in rats. Using a previously established scoring system, 12 withdrawal signs (chewing, sniffing, grooming, wet-dog shakes, stretching, yawning, rearing, jumping, teeth grinding, ptosis, diarrhea, and penile erection) were observed and scored after a naloxone (4 mg/kg i.p.) challenge. Endomorphins (20 µg i.c.v., b.i.d. for 5 days) were shown to induce physical dependence, but they displayed different potency for certain signs. The severity of the endomorphin-induced withdrawal was similar to that induced by the same dose of morphine.

Unfortunately, no data on the interactions between endomorphins and the nonopioid systems are available, although dopamine (DA) (El-Kadi and Sharif, 1998; Samini et al., 2000; Tokuyama et al., 2000), NA (Milanes et al., 1998; Fuentealba et al., 2000; Fuertes et al., 2000; Laorden et al., 2000), ACh (Zhang and Buccafusco, 1998; Buccafusco et al., 2000), benzodiazepine (Tejwani et al., 1998), N-methyl-D-aspartate (Popik et al., 1998), imidazoline (Su et al., 2000), Glu (Rockhold et al., 2000), and GABAergic (Sayin et al., 1998) pathways were suggested to play an important role in the development of physical dependence. Nitric oxide (NO) may also be involved in endomorphin-induced dependence, both directly, as systemic injections of NO synthase inhibitors attenuated some signs of naloxone-precipitated withdrawal and hyperactivity of the LC (Pineda et al., 1998), and indirectly, as the i.t. infusion of morphine increased N-methyl-D-aspartate binding activity and up-regulated neuronal NO synthase expression (Wong et al., 2000).

4. Effects on Locomotor Activity. The effects of opioid receptor ligands on locomotor activity are influenced by a number of variables, including the dose and the paradigm used in the experiment. However, in most studies the µ- and -opioid receptor ligands stimulated locomotor activity by increasing the synthesis and the release of DA from dopaminergic neurons in the nigrostriatal and the mesolimbic dopaminergic system (Chesselet et al., 1981; Urwyler and Tabakoff, 1981; Broderick, 1985; Locke and Holtzman, 1986; Cunningham and Kelley, 1992). In contrast, -opioid receptor agonists were shown to decrease both vertical and horizontal locomotion (Kuzmin et al., 2000).

The opioid alkaloid morphine, a µ-opioid receptor ligand with low affinities to - and -opioid receptors, was shown to increase locomotion under most conditions (Latimer et al., 1987; Austin and Kalivas, 1990; Calenco-Choukroun et al., 1991; Aguilar et al., 1998; Kimmel et al., 1998; Schildein et al., 1998; Stinus et al., 1998), but in some cases had no effect (Waddell and Holtzman, 1998). Acute injections of morphine stimulated horizontal locomotion through the µ-opioid receptors and grooming through the -opioid binding sites, localized in the VTA, Nac, and PAG (Babbini and Davis, 1972; Joyce and Iversen, 1979; Katz, 1979; Havemann et al., 1983; Morgan et al., 1998; Schildein et al., 1998). A single administration of morphine was shown to increase behavioral sensitivity to the DA agonist, apomorphine (de la Baume et al., 1979), whereas chronic treatment resulted in the development of supersensitive DA receptors, as determined by induction of the stereotypic behaviors by the DA agonists (Ritzmann et al., 1979). To elucidate the relationship between morphine and DA, Jang et al. (2001) compared the effect of morphine on the modulation of the apomorphine-induced climbing behavior in wild-type and µ-receptor knockout mice. Treatment with morphine potentiated apomorphine-induced climbing behavior in wild-type mice, whereas it did not produce any significant effect in the µ-receptor knockout mice. These results indicated that µ-receptors play an important role in potentiation of the climbing behavior induced by DA receptor agonists (Jang et al., 2000) and proved that µ-receptor ligands influence the dopaminergic system.

Effects of centrally administered endomorphin-1 and endomorphin-2 on locomotor activity were evaluated and seem confusing. In some studies endomorphins, like morphine, were shown to increase horizontal and vertical activity (i.e., hyperlocomotion) and not to alter grooming activity (Bujdoso et al., 2001, 2003). Interestingly, the concentration-response curves for endomorphin-1 and endomorphin-2 in mice were of a bell-shaped type (Bujdoso et al., 2001). However, relatively lower concentrations of endomorphin-2 than of endomorphin-1 were used to obtain the same response (Bujdoso et al., 2001), suggesting differences in activation of the µ-opioid receptor subtypes (Sakurada et al., 1999, 2000) or the involvement of the enkephalinergic or dynorphinergic system (Sanchez-Blazquez et al., 1999; Tseng et al., 2000).

In contrast, some studies showed that endomorphins did not influence locomotor activity. Our group (Fichna et al., 2007) investigated the effect of i.c.v. administration of endomorphin-1 and endomorphin-2 on locomotor activity in mice. The peptides did not modify horizontal locomotor activity in any of the time periods of the test. Furthermore, endomorphin-1, at the highest dose (30 µg/mouse), and endomorphin-2, at the lowest doses (0.3 and 1 µg/animal), produced weak inhibition of vertical locomotor activity.

Our results are consistent with those obtained by Mehta et al. (2001), who examined the influence of endomorphins on the activity of basal ganglia, specific subcortical brain structures that play an important role in the control of movement (Delfs et al., 1994; Peckys and Landwehrmeyer, 1999). Dysfunction of the basal ganglia, resulting from specific degeneration of neurons, as in Parkinson's and Huntington's diseases, or from the administration of pharmacological agents, leads to severe motor disorders (Albin et al., 1991; Chesselet and Delfs, 1996). Within the basal ganglia, a subpopulation of neurons of the globus pallidus expresses particularly high levels of µ-opioid receptor mRNA (Delfs et al., 1994; Obeso et al., 2000). Morphine injections into the globus pallidus produced a robust increase in locomotor activity (Anagnostakis et al., 1992), whereas endomorphin-1 induced orofacial dyskinesia (Mehta et al., 2001). The authors of that report suggested that stimulation of the locomotor activity by morphine could be mediated by - and -opioid receptors and the inhibitory activity of endomorphin-1 might involve µ-opioid receptors. Previous studies showed that stimulation of GABA receptors induced catalepsy in rats (Egan et al., 1995). Endomorphin-1 and GABA could therefore induce opposite behavioral effects in the globus pallidus and alterations in their equilibrium could play a crucial role in control of movement and development of dyskinesia.

5. Behavioral Sensitization. Repeated administration of psychoactive drugs can lead either to a decrease (tolerance) or an increase (sensitization) in their behavioral effects. The term "behavioral sensitization" was first used to describe the augmented motoric stimulant effect produced by a given dose of a psychomotor-stimulant drug, such as amphetamine or cocaine, after repeated intermittent injections (Segal and Kuczenski, 1997). This phenomenon could persist for a long period after drug abstinence (Robinson and Becker, 1986). The term is now more readily used for the phenomenon of increased behavioral and neurochemical responsiveness of any type to the administration of the same or lower doses of drug after repeated drug injections (Spyraki et al., 1983).

Behavioral sensitization plays an important role in the development and maintenance of drug addiction (Gaiardi et al., 1991; Hunt and Lands, 1992; Robinson and Berridge, 1993); simple "preference" for a drug becomes "sensitized" (i.e., increases) up to the point where the urge to take the drug becomes overwhelming (i.e., loss of behavioral control or drug craving) (Wise and Bozarth, 1987; Robinson and Berridge, 1993). Virtually all human drugs of abuse that show positive results in animal models of reward and addiction produce behavioral sensitization (Stewart and Badiani, 1993).

In the search for neuroanatomical and neurochemical bases of drug-induced sensitization, research has focused on the mesolimbocortical dopaminergic pathway, which arises in the VTA and projects mainly to the Nac (Spanagel, 1995). There are several transmitter systems in the VTA known to evoke behavioral sensitization, including DA (Hooks et al., 1993, Hooks and Kalivas, 1994'02; Vezina, 1996), GABA (Johnson and North, 1992), Glu/aspartate (Karler et al., 1990), and tonically active endogenous opioid systems (Spanagel et al., 1992).

In vivo DA release measurements (microdialysis) clearly demonstrated that systemic administration of µ-opioid receptor agonists increases DA release in the Nac (Di Chiara and Imperato, 1988a,b; Spanagel et al., 1990; Pentney and Gratton, 1991). DAMGO and morphine increased DA release in the Nac after injection into the VTA (Leone et al., 1991; Longoni et al., 1991; Spanagel et al., 1992; Devine et al., 1993), whereas D-Phe-c(Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂) (CTOP)], a highly specific µ-opioid receptor antagonist, produced a significant decrease of DA release in the Nac (Spanagel et al., 1992). In contrast, infusion of either ligand into the Nac was without any effect.

Chen et al. (2001) reported that repeated administration of endomorphins in the VTA has a significant effect on the development of sensitization to amphetamine in rats. To understand the neural basis of the behavioral outcome of the chronic endomorphin treatment, the tissue contents of several neurotransmitters and their metabolites in the limbic forebrain (ventral striatum and medial prefrontal cortex) and extrapyramidal area (dorsal striatum) of rats treated with amphetamine or endomorphin were analyzed. It has been demonstrated that Glu concentrations increased significantly in all tested brain areas in both groups of animals. It was suggested that µ-opioid receptor agonists could activate dopaminergic neurons through the activation of GABA or Glu neurons in the VTA (Karler et al., 1990, Wolf and Xue, 1998; Johnson and North, 1992).

6. Drug Addiction, Mechanism of Reward. Numerous studies, in which µ-selective agonists and antagonists were used, showed that the µ-opioid receptor is the primary factor in the development of drug addiction because of its central role in the mediation of reward (Negus et al., 1993, Devine and Wise, 1994; Piepponen et al., 1997). µ-Opioid receptor ligands, including DAMGO, morphine, codeine, and sufentanyl, elicited strong rewarding effects in several brain structures, such as the VTA or Nac (for review, see Wise, 1989; Suzuki, 1996; Martin-Schild et al., 1999), whereas selective -opioid receptor agonists produced significant aversion (Becker et al., 2000). The µ-opioid receptor agonists were also shown to mediate the reward effects induced by stress (Zacharko et al., 1998).

It is generally assumed that the critical brain region for µ-opioid effects on motivation is the VTA. The rewarding effects of µ-opioid injections into the VTA are mediated by the µ-opioid receptors expressed on the GABA-containing cells. µ-Opioid receptor agonists inhibit GABAergic inputs to the dopaminergic VTA principal cells, projecting to the Nac, and disinhibit release of DA in the Nac, a major component of the endogenous reward circuitry of the brain (Johnson and North, 1992; Margolis et al., 2003).

Similarly to morphine and DAMGO, endomorphins injected into the posterior VTA established a conditioned place preference and produced significant psychomotor stimulating effects (Zangen et al., 2002). Endomorphin-1 injected into the posterior VTA gave also strong rewarding effects in the self-administration paradigm. Injection of endomorphin-1 and DAMGO into the Nac gave no rewarding effect (Zangen et al., 2002). The effect of DAMGO was not only weak but also generally delayed, which suggests the lack of sites of action for µ-opioid agonists in the Nac (Churchill and Kalivas, 1992; Johnson et al., 1996; Churchill et al., 1998).

The possible rewarding effect of i.c.v.-administered endomorphins has also been investigated in different species; however, the results obtained were inconsistent. Narita et al. (2001a,b) reported that endomorphin-1 produced a significant place preference and endomorphin-2 produced a significant place aversion in mice, which were inhibited by pretreatment with either an antiserum against the endogenous -opioid receptor agonist dynorphin A(1-17) or coadministration with a -opioid receptor antagonist (Wu et al., 2004). The authors suggested that endomorphins stimulate different subtypes of the µ-opioid receptor and that endomorphin-2 could additionally stimulate the release of dynorphins, which are responsible for its aversive effect (Fig. 6).

View larger version (25K): [in this window] [in a new window]   FIG. 6. Different motivational effects of endomorphin-1 (EM-1) and endomorphin-2 (EM-2). DYN A, dynorphin A. Adapted from Narita et al. (2002).

Recently, an important role of the µ-opioid receptors located in the PAG in morphine-induced aversion has been suggested (Sante et al., 2000). Moreover, an integrative model of addiction, which emphasized the relationship between chronic opioid administration, disruption of the hypothalamo-pituitary-adrenal (HPA) axis, and dysregulation of brain reward systems, has been proposed (Kreek and Koob, 1998). However, the possible involvement of endomorphins in both systems has not been yet characterized.

7. Psychiatric disorders.
a. Stress. So far, the precise role of endogenous opioid peptides and opioid receptors in the response to stress stimuli has not been fully elucidated. However, many stressors were shown to interact with the endogenous opioid system (Baumann et al., 2000; Huang et al., 2000; Jamurtas et al., 2000; LaBuda et al., 2000; Matsuzawa et al., 2000; Spreekmeester and Rochford, 2000; Takahashi et al., 2000; Van den Berg et al., 2000), and therefore a close relationship between the level of the opioid receptor ligands, corticosteroids, and related hormones has been proposed.

The HPA axis seems to play the major role in the stress response. The activation of the HPA axis by different stimuli (stress, immune challenge, and others) causes increased secretion of corticotrophin-releasing factor (CRF) and arginine vasopressin (AVP) from the median eminence of the hypothalamus. In turn, these neuropeptides stimulate the secretion of adrenocorticotropin (ACTH) from the anterior lobe of the pituitary (Coventry et al., 2001). Elevated levels of ACTH stimulate the production and release of glucocorticoids from the adrenal glands into the circulation, which then exert negative feedback actions on the pituitary and other target areas in the CNS, thus regulating the HPA axis activation (Harbuz and Lightman, 1989).

The role of the µ-opioid receptor ligands in the control of the HPA axis remains ambiguous. Some authors claim that the stress-responsive HPA axis is under tonic inhibition via endogenous β-endorphin and the µ-opioid receptors in the hypothalamus (Nikolarakis et al., 1987; Kreek et al., 2002). In contrast, it has been demonstrated in rat that acute administration of morphine increased ACTH and corticosterone levels in plasma (Ignar and Kuhn, 1990) and that morphine acts primarily through µ-receptors to activate the HPA axis (Mellon and Bayer, 1998).

Centrally administered endomorphins did not stimulate the HPA axis and had no effect on corticosterone release, although it was injected at a dose of 10 µg, which is sufficient to activate other physiological systems (Coventry et al., 2001). In addition, endomorphin-1 failed to block the stimulatory effects of morphine on the plasma corticosterone level. Furthermore, activation of the HPA axis did not influence the plasma level of endomorphins in rats exposed to the chronic inflammatory stress of adjuvant-induced arthritis, the psychological stress of restraint, and the immunological stress of lipopolysaccharide, although plasma corticosterone, ACTH, and β-endorphin increased. These results suggested that endomorphins do not play an important role in mediating the stress response or regulating the HPA axis. If activation of the HPA axis is indeed mediated by µ-opioid receptors, the lack of an endomorphin-induced effect might be due to the differences in diffusion and metabolism of these peptides, compared with morphine. Another possible explanation is that the µ-receptor agonists have different patterns for the stimulation of the G-proteins coupled to the µ-binding sites, as was shown in animal models of pain (Sanchez-Blazquez and Garzon, 1988; Sanchez-Blazquez et al., 1999).

In contrast, subsequent studies showed a close relationship between endomorphins and the HPA axis. Champion et al. (1999a) provided strong evidence that the release of the gaseous neurotransmitter, NO, which plays an important role in mediation of the physiological actions of morphine (Granados-Soto et al., 1997) and other opioids (Gholami et al., 2002), is responsible for the vasodilatory action of the endomorphins. Bujdoso et al. (2003) suggested that a much broader range of endomorphin actions is mediated by NO, including activation of the HPA system, and introduced the term of "endomorphin-NO-HPA axis" (Calignano et al., 1993; Bujdoso et al., 2003) (Fig. 7).

View larger version (16K): [in this window] [in a new window]   FIG. 7. Possible implications of endomorphins in the activation and the control of the HPA axis in the stress response.

Hui et al. (2006) demonstrated that the NTS, through endomorphin-containing ascending fibers, might exert modulatory functions in the hypothalamus, a critical element of the HPA axis (Ter Horst et al., 1989; Boscan et al., 2002). Likewise, the hypothalamus might directly influence the NTS via endomorphinergic descending fibers. Therefore, endomorphins might be involved in activation of the HPA axis and release of CRF, a major mediator of the stress response (Swanson, 1987; Saper, 1995).

The PAG is yet another brain structure likely to be implicated in the stress response, as it was shown to mediate stress-induced immobility and analgesia in adult rats and rat pups (Wiedenmayer and Barr, 2000). Experiments with the general opioid receptor antagonist naltrexone and the selective µ-opioid receptor antagonist CTOP demonstrated that the analgesic effect was produced by endogenous opioids that bind to µ-opioid receptors in the ventrolateral PAG. Perhaps endomorphins might also be involved in the PAG-mediated stress-induced analgesia.

b. Anxiety. There are several reports on the anxiolytic action of morphine and µ-opioid receptor agonists, injected both centrally (File and Rodgers, 1979; Fanselow et al., 1988; Costall et al., 1989; Motta et al., 1995) and peripherally (Millan and Duka, 1981; Koks et al., 1999; Zarrindast et al., 2005), and the anxiogenic effect produced by µ-opioid receptor antagonists (Tsuda et al., 1996). The effects of morphine are dose- and site-dependent: morphine injected into the midbrain tectum of rats at low doses produced anxiolytic-like effects, but at high doses displayed an anxiogenic-like activity (Brandao et al., 1999); when injected to the rat dorsal PAG (Nobre et al., 2000) and lateral septum (Le Merrer et al., 2006), morphine produced dose-dependent aversive effects.

The anxiolytic action of µ-opioid ligands is mediated by their interaction with the GABAergic system in some specific brain areas (Sasaki et al., 2002), the amygdala being one of these (Kang et al., 2000; Sasaki et al., 2002). Other studies on anxiety-related behavior in animals suggested the involvement of serotonergic, benzodiazepine, and neuropeptide receptors (for reviews, see Rodgers and Cole, 1993; Griebel, 1995, 1999; Menard and Treit, 1999).

A high degree of homology between the neuroanatomical distribution of endomorphins and the localization of µ-opioid receptors in the areas important for motivation, arousal, and vigilance, namely the paraventricular nucleus, septum, lateral hypothalamus, dorsomedial nucleus of the hypothalamus, LC, and amygdala (Stanley et al., 1988), suggests that they might be involved in the modulation and expression of anxiety- or stress-induced behaviors. The only report on endomorphin and anxiety, published by Asakawa et al. (1998), showed that i.c.v. administered endomorphin-1 increased the preference for the open arms of the elevated plus maze and produced an anxiolytic effect in mice. This observation is in good agreement with previous reports stating that µ-opioid receptor agonists produce drowsiness and feelings of warmth and well-being (Tsuda et al., 1996).

c. Depression and other psychiatric disorders. According to Vaccarino et al. (1999), interest in the possible role of opioid systems in modulation of mental illness and mood continues to decline. A likely contributing factor is the failure to demonstrate any clear global therapeutic benefit from treatment with opioid ligands, thus obscuring the role of endogenous opioid systems in mediation of mental illnesses. However, the available data clearly demonstrate that the µ-opioidergic system is considerably involved in the etiology of mental disorders, thus providing a rationale for the use of µ-opioid ligands in behavioral therapies.

High concentrations of µ-opioid receptors and their endogenous ligands were observed in the limbic areas involved in regulation of mood and stress responses (Belenky and Holaday, 1979; Waksman et al., 1986; Mansour et al., 1988; Bodnar and Klein, 2004). Moreover, µ-opioid receptor knockout mice were shown to have an altered emotional state, consistent with depressed mood (Filliol et al., 2000). Clinical studies revealed that there is an increased level of β-endorphin and µ-opioid receptors in plasma and brain of the patients suffering from depression and schizophrenia (Lindstrom et al., 1978; Gross-Isseroff et al., 1990; Scarone et al., 1990; Darko et al., 1992; Gabilondo et al., 1995).

However, no differences in β-endorphin plasma levels between manic, depressed, or neurotic patients and healthy volunteers were found (Emrich et al., 1979). Therefore, the theory, based on the observation that opiates exert euphorogenic effects in healthy volunteers (Byck, 1976; Kline et al., 1977), suggesting that the endogenous depression would represent a state of dysfunction of the opioidergic system (e.g., in limbic structures), whereas mania would be considered as a state of opioidergic hyperactivity (Byck, 1976; Belluzzi and Stein, 1977), is no longer in use.

Numerous reports showed that a wide variety of µ-opioid receptor agonists may act as antidepressant agents (Kraepelin, 1905; Kline et al., 1977; Kastin et al., 1978; Mansour et al., 1988; Darko et al., 1992; Bodkin et al., 1995; Tejedor-Real et al., 1995; Besson et al., 1996; Stoll and Rueter, 1999; Makino et al., 2000a,b; Vilpoux et al., 2002). Since the work of Kraepelin (1905), opium has been recommended for the treatment of depressed patients. Kline et al. (1977) performed clinical trials on patients with different types of psychiatric disorders (schizophrenia, depression, and neuroses) and observed an antidepressant effect of β-endorphin. The µ-opioid receptor agonists, oxycodone and oxymorphone, administered chronically for several months, were shown to act as antidepressants without causing opioid tolerance or dependence (Stoll and Rueter, 1999). Similarly, morphine produced a significant antidepressant-like effect in the forced swimming test after s.c. injections (Eschalier et al., 1987). Naloxone, a universal opioid antagonist, was shown to reverse the effect of anticonvulsive therapy in depressed patients, one of the most effective treatments in severe depression (Belenky and Holaday, 1979). However, treatment with naloxone administered alone produced neither a significant change in healthy volunteers (Grevert and Goldstein, 1978) nor an effect on manic or depressive disorders (for review, see Emrich, 1982).

In view of the fact that endomorphins and the µ-opioid receptors are colocalized in the brain regions involved in the physiopathology of depression, such as the limbic system (the septum, Nac, and amygdala), the thalamic nuclei, LC, and some regions of the brainstem (Schreff et al., 1998; Martin-Schild et al., 1999; Zadina, 2002), it was suggested that these peptides could play an important role in the etiology of depressive disorders. However, although various studies associated the µ-opioidergic system and the antidepressant actions, it was only recently that the antidepressant effect of endomorphins was clearly verified.

In our study (Fichna et al., 2007), endomorphin-1 and endomorphin-2 (0.3–30 µg/animal i.c.v.) produced significant antidepressant-like activity in the forced swimming test (FST) and the tail suspension test in mice. These effects were dose-dependent and short-lasting; a significant response was observed only 10 and 15 min after i.c.v. administration. The magnitude of the effect induced by endomorphins was comparable to that observed after the treatment with well-known antidepressants and the compounds with potential antidepressant-like activity (Cryan et al., 2005; Petit-Demouliere et al., 2005). In contrast with the effect of other µ-opioid receptor agonists (Babbini and Davis, 1972), the antidepressant-like effect of endomorphins did not result from stimulation of animal motor activity: the peptides did not increase the horizontal locomotor activity evaluated in a new environment. We have even observed a weak tendency to decrease vertical movements. This result is in good agreement with the classic observations that antidepressants reduce immobility in the forced swimming test at doses that do not cause stimulation of locomotion (Porsolt et al., 1977) or even tend to decrease locomotor activity (Duterte-Boucher et al., 1988; Bourin, 1990).

We also demonstrated that both naloxone, a reference opioid receptor antagonist with a relatively high affinity toward µ-opioid receptors, and β-funaltrexamine, a selective µ-opioid receptor antagonist, significantly antagonized the antidepressant-like effect of endomorphins. In contrast, neither naltrindole, a selective -opioid receptor antagonist, nor nor-binaltorphimine, a selective -opioid receptor antagonist, was able to block the antidepressant-like effect of endomorphins. These results indicated that the effect of endomorphins is mediated, in great part, through central µ-opioid receptors.

There is one more recent study on the possible involvement of endomorphins in the pathophysiology of depression. Zhang et al. (2006) examined the effects of i.c.v. administered endomorphins, at doses active in other behavioral studies (30 and 90 nmol/animal, i.e., 20 and 50 µg/animal), on animal behavior in the FST and on brain-derived neurotrophic factor (BDNF) gene expression in rats. BDNF, a neurotrophic factor from the nerve growth factor family, regulates neuronal survival, differentiation, and plasticity (Binder and Scharfman, 2004). Several lines of evidence suggest that the BDNF plays an important role in the pathophysiology of depression and in the mechanism of therapeutic actions of antidepressants (Siuciak et al., 1997; D'Sa and Duman, 2002; Shirayama et al., 2002; Shimizu et al., 2003; Castren, 2004; Hashimoto et al., 2004). Studies revealed that endomorphins do not influence the time of the animal immobility in the FST in rats. However, centrally administered endomorphins significantly increased BDNF gene expression in the frontal cortex, hippocampus, and amygdala in a dose-dependent manner. Moreover, the opioid receptor antagonist naltrexone completely blocked the increase in BDNF mRNA expression produced by endomorphin-1 in all brain regions and blocked the effect of endomorphin-2 in the frontal cortex. In contrast, the -opioid receptor antagonist naltrindole showed little or no antagonist effect against both peptides. Taken together, these results show that endomorphins produced contradictory effects: they were shown to up-regulate BDNF mRNA expression in the rat brain through the activation of the central µ-opioid receptor and to lack antidepressant-like behavioral effects.

Both this inconsistency and the disagreement with our results may be easily explained by observation of the time course of endomorphin effects. Zhang et al. (2006) performed the FST 30 min after central administration of endomorphins, which is far too late. As was shown in our report, endomorphins, because of rapid enzymatic degradation, produced a significant antidepressant effect only 10 to 15 min after i.c.v. administration. For this reason, no antidepressant activity was observed beyond that period of time.

8. Social Defeat. In a number of animal models of social defeat, the subordinate animal shows signs of stress as indicated by physiological, neuroendocrine, neurochemical, and behavioral changes (Martinez et al., 1998). Physiological changes after defeat include increases in blood pressure and heart rate (Bohus et al., 1990; Meehan et al., 1995), as well as activation of the HPA axis (Miczek et al., 1991; Blachard et al., 1993). Behaviorally, defeat leads to decreases in activity (Raab et al., 1986; Kudryavtseva et al., 1991) and social interaction (Van de Poll et al., 1982; Kudryavtseva, 1994; Avgustinovich et al., 1996), as well as aggression (Potegal et al., 1993; Albonetti and Farabollini, 1994; Avgustinovich et al., 1996), and increases in defense (Andrade et al., 1989; Potegal et al., 1993), anxiety (Andrade et al., 1989; Heinrichs et al., 1992), and drug seeking (Haney et al., 1995). These behavioral changes are thought to be related to fear, anxiety, depression, and panic (Blanchard et al., 1998a,b).

The µ-opioid agonists might play a critical role in the behavioral response to defeat. It was demonstrated that µ-opioid receptor up-regulation in the VTA occurs after social defeat (Nikulina et al., 1999), and defeat-induced ultrasonic vocalizations are decreased by µ-receptor agonists (Vivian and Miczek, 1998). Whitten et al. (2001) tested the hypothesis whether endomorphin-1 inhibits the expression and/or consolidation of conditioned defeat in Syrian hamsters. Intracerebroventricular administration of endomorphin-1 reduced the expression of conditioned defeat without stimulating locomotor activity or inducing sedation. The following mechanisms of action were suggested: 1) inhibition of memory retrieval, which was observed for other µ-agonists, such as Tyr-D-Arg-Phe-β-Ala (Ukai et al., 1995a) and morphine (Saha et al., 1991); 2) modulation of normal animal response to fear or anxiety (Asakawa et al., 1998), similar to that elicited by morphine and DAMGO, which exert anxiolytic activity in rats (File and Rodgers, 1979; Motta and Brandao, 1993; Motta et al., 1995; Koks et al., 1999); and 3) inhibition of noradrenergic neurons, because an opposite effect was observed for the µ-receptor antagonist naloxone (Introini and Baratti, 1986). Intracerebroventricular administration of endomorphin-1 failed to inhibit the consolidation of conditioned defeat, whereas morphine was shown to impair the consolidation of newly acquired memories in rats and mice (Izquierdo, 1979; Introini et al., 1985; Castellano et al., 1994; Cestria and Castellano, 1997; Rudy et al., 1999). Again three possibilities were proposed: 1) the endomorphin-1 dose used was too low; 2) the time of exposure to endomorphin-1 was not long enough to develop consolidation; and 3) the interaction with the µ-receptor could result in secondary messenger cascade different from that activated by morphine.

9. Food Intake. Central mechanisms regulating food intake are complex and only a few peptides, including neuropeptide Y, growth hormone-releasing factor, orexin, and 26RFa were shown to possess orexigenic activity (Morley et al., 1983; Clark et al., 1984; Vaccarino et al., 1985; Inui et al., 1991; Sakurai et al., 1998; Chartrel et al., 2003).

The opioid receptor agonists display well-documented effects on feeding behavior. They tend to increase food intake, namely that of sucrose (Higgs and Cooper, 1998), other carbohydrates (Zhang et al., 1998), or fat (Higgs and Cooper, 1998; Zhang et al., 1998) in rodents exposed to different environmental conditions (Giraudo et al., 1998a,b; Itoh et al., 1998; Leventhal et al., 1998a,b; Zhang et al., 1998). The µ-opioid receptor agonists, which also exhibit orexigenic activity (Morley et al., 1982; Woods and Leibowitz, 1985; Gosnell et al., 1986; Glass et al., 1999), modulate feeding behavior and gustatory information through µ-opioid receptors located in the hypothalamus (Pfeiffer and Herz, 1984; Kuhn and Windh, 1989) and NTS (Matsuo et al., 1984; Moufid-Bellancourt and Velley, 1994).

As observed for the µ-opioid receptor ligands, morphine and DAMGO, i.c.v. injection, in nonfood-deprived mice of either endomorphin-1 or endomorphin-2 (0.03–30 nmol) increased food intake in a dose-related manner for up to 4 h after injection (Asakawa et al., 1998). Similarly to the morphine metabolite, morphine-6β-glucuronide, the effect of endomorphins was dose dependently attenuated by a µ-opioid receptor antagonist, β-funaltrexamine, and not by -or -antagonists (Leventhal et al., 1998a,b). However, a -opioid receptor-selective agonist, dynorphin A, was more potent than endomorphins in stimulating food intake. These observations confirmed that the orexigenic activity of endomorphins is mediated by µ-opioid receptors and suggested that µ-opioid receptor agonists play a rather minor role in this phenomenon.

10. Sexual Behavior. There is an extensive evidence for the involvement of the endogenous opioid system in the regulation of pregnancy, parturition, and reproductive functions in female rats (Pfaus and Gorzalka, 1987a; Argiolas, 1999; Gilbert et al., 2000). Both direct and indirect actions of opioids on gonadal hormones were demonstrated: endogenous opioid peptides activate specific receptors within the interconnected limbic-hypothalamic reproductive behavior-regulating circuits to mediate facilitatory and inhibitory effects of sex steroids (Sinchak and Micevych, 2001). Moreover, the administration of opiates and opioid peptides influenced gonadotropin release (Bakker and Baum, 2000) and altered female rat sexual behavior (Wiesner and Moss, 1984, 1986; Sirinathsinghji, 1985, 1986; Pfaus et al., 1986; Forsberg et al., 1987; Vathy et al., 1991).

The influence of µ-opioid receptor-selective ligands on female reproduction is complex. The immunocytochemical data showed that µ-opioid receptors are widely distributed in some areas involved in female reproductive behavior, such as the ventromedial hypothalamus (VMH), the medial preoptic area (mPOA), and the mesencephalic central gray (MCG) (Pfaff et al., 1994; Martin-Schild et al., 1999). Concurrently, µ-opioid receptor-selective ligands were shown to possess a dual effect on lordosis, a hormone-related behavior displayed by hormonally primed female rodents during mating (Pfaff et al., 1994), depending on the concentration used and the route of administration (Wiesner and Moss, 1984; Sirinathsinghji, 1986; Pfaus and Gorzalka, 1987a,b; Vathy et al., 1991; Pfaff et al., 1994; Van Furth et al., 1995). For example, low doses of β-endorphin inhibited lordosis in gonadectomized, steroid-primed female rats when infused into the third ventricle (Wiesner and Moss, 1984, 1986), lateral ventricles (Pfaus et al., 1986; Pfaus and Gorzalka, 1987b), the MCG (Sirinathsinghji, 1984, 1985), or mPOA (Sirinathsinghji, 1986). On the contrary, β-endorphin and morphiceptin at high doses facilitated lordosis in estrogen- or estrogen- and-progesterone primed rats after infusions into the third or lateral ventricles (Pfaus et al., 1986; Pfaus and Gorzalka, 1987b; Torii and Kubo, 1994; Torii et al., 1997, 1999).

Reports on the influence of endomorphins on the reproduction behavior are sparse. Sinchak and Micevych (2001) investigated the role of µ-opioid receptors and their ligands in the progestin-induced lordosis in nonreceptive female rats treated with estrogen. They showed that endomorphin-1, infused into the mPOA, inhibited lordosis through the activation of the µ-opioid receptors in the mPOA.

In another study, Acosta-Martinez and Etgen (2002) used endomorphins to investigate at which brain site(s) µ-opioid receptor activation affects lordosis behavior in hormonally primed female rats. Administration of endomorphin-1 and endomorphin-2 into the third ventricle resulted in a dose- and time-dependent, naloxone-reversible attenuation of lordosis behavior in rats. None of the tested peptides inhibited lordosis when infused into the VMH, mPOA, or MCG. Interestingly, endomorphins significantly inhibited lordosis behavior in animals, whose bilateral infusion cannulae were located at the ventral part of the medial septum-horizontal limb of the diagonal band (MS-HDB). Because both endomorphin IR and µ-opioid receptors were found in the MS-HDB (Loughlin et al., 1995; Martin-Schild et al., 1999) and the fibers from the MS-HDB were shown to innervate the mPOA and several hypothalamic nuclei (Jakab and Leranth, 1995), brain regions previously linked to the inhibition of lordosis by opiates, it was proposed that the MS-HDB is the major site of action of endomorphins on lordosis behavior. Moreover, because luteinizing hormone releasing hormone-, ACh-, and GABA-containing cells are present in the MS-HDB (for review, see Pfaff et al., 1994), it is possible that endomorphins could inhibit lordosis by modulating the release of any of these factors.

11. Learning and Memory. A variety of endogenous systems are considered to be involved in learning and memory. These include the opioid system, which has been demonstrated in operant and classic conditioning, as well as in various cognitive tasks to play an important role in the memory processes and memory storage. The µ-opioid receptor agonists, DAMGO and Tyr-D-Arg-Phe-β-Ala, and the -selective opioid receptor agonists [D-Pen²,L-Pen⁵]enkephalin and [D-Ala²]deltorphin II, were demonstrated to impair short-term memory and passive avoidance learning, associated with long-term memory processes (Ukai et al., 1993b, 1997; Itoh et al., 1994). Activation of µ-opioid receptors in the septal nuclei has been reported to affect spatial memory (Bostock et al., 1988). The -agonist dynorphin A(1-13) reversed the disturbance of learning and memory in aversive and nonaversive tasks (Ukai et al., 1993a). The opioid receptor antagonists enhanced memory retention (Ferry and McGaugh, 2000).

There is a growing body of evidence on the involvement of endomorphin-1 and endomorphin-2 in learning and memory. However, to the best of our knowledge, only a single report on the role of both peptides in short-term memory processes has been published so far. Ukai et al. (2000) demonstrated that endomorphins impair spontaneous alternation performance in mice, which is associated with short-term memory.

The effects of endomorphin-1 and endomorphin-2 on impairment of passive avoidance learning, based on the long-term memory processes, were also established. Ukai and Lin (2002a,b) demonstrated that both peptides, after i.c.v. administration, significantly shortened the step-down latency in the passive avoidance learning task in mice. Endomorphin-induced inhibitory activity was attenuated by the selective µ-opioid receptor antagonist, β-funaltrexamine, whereas the µ₁-receptor antagonist, naloxonazine, fully reversed the effect of endomorphin-1 but not that of endomorphin-2. These data demonstrated that endomorphin-1 impaired long-term memory through µ₁-opioid and endomorphin-2 through µ₂-opioid receptors.

Freeman and Young (2000) demonstrated that passive avoidance learning in chicks disrupted by endomorphin-2 may involve cytosolic and mitochondrial protein synthesis within the lobus paraolfactorius, which constitutes a structure homologous to the caudate putamen in mammals (Veenman et al., 1995; Metzger et al., 1996; Durstewitz et al., 1999). Endomorphin-2 was shown to reverse the amnesic effects of anisomycin and blocked cytosolic protein inhibition in this structure. However, Ukai et al. (2001) suggested that endomorphin-induced inhibition of passive avoidance learning resulted from functional disconnection of the hippocampus, which is believed to be important for converting new memories into long-term memories.

There could be at least two neurotransmitter systems, which could contribute to the endomorphin-induced impairment of long-term memories, namely cholinergic and dopaminergic, although their precise role has not been elucidated. For example, it was shown that both peptides significantly decreased ACh release in the brain areas associated with memory processes, and this effect was mediated by µ-opioid receptors (Ragozzino et al., 1994), which is in good agreement with the observation that spatial working memory involves an interaction between opioid and ACh systems (Kameyama et al., 1998). Moreover, endomorphin-induced impairment of passive avoidance learning was reversed by physostigmine, a classic cholinesterase inhibitor (Itoh et al., 1994; Ukai and Lin, 2002b). Alternatively, Ukai and Lin (2002a) demonstrated that the dopamine D₂-receptor antagonist attenuated endomorphin-2-induced impairment of passive avoidance learning and suggested that the inhibitory effect of endomorphin-2 resulted from the stimulation of D₂-receptors, probably in the dopaminergic pathways projecting into the striatum or Nac during the process of acquisition and/or consolidation of memory. They also proposed that there is a similarity between endomorphin-2- and scopolamine-induced memory impairment, as the effects of both are mediated through the D₂-receptors.

Recently, centrally administered endomorphin-1 and -2 were shown to increase BDNF mRNA expressions in hippocampus and amygdala (Zhang et al., 2006). BDNF participates in synaptic plasticity mechanisms, such as long-term potentiation, learning, and memory (Huang and Reichardt, 2001; Malcangio and Lessmann, 2003). These observations may suggest a link between endomorphins, µ-opioid receptors, and BDNF in learning and memory.

12. Effects on Cardiovascular System. Many neuroanatomical regions within the brain, which regulate cardiovascular activity, contain opioid receptors and/or endogenous opioid peptides. These include the ventral lateral medulla, NTS, lateral hypothalamus, paraventricular nucleus (PVN), dorsal hippocampus, and integral parts of the limbic system. Endogenous opioid systems play an important role in mediating cardiovascular responses. However, the reported effects of opioid receptor ligands on blood pressure and heart rate are confusing. Direct injections of µ-, -, and -opioid receptor agonists into the PVN, dorsal hippocampus, and rostral ventrolateral medulla of normotensive and spontaneously hypertensive rats demonstrated that, in general, µ- and -agonists reduced heart rate and blood pressure (Sun et al., 1996). Intracerebroventricular administration of the µ-opioid receptor agonists, morphine, β-endorphin, and DAMGO, also induced hypotension in a variety of species (Holaday, 1983; Johnson et al., 1985; Unal et al., 1997; Champion et al., 1998a,b; Olson et al., 1998; Vaccarino et al., 1999).

Similarly, endomorphin-1 and endomorphin-2 lowered heart rate and decreased blood pressure in normotensive and spontaneously hypertensive rats (Champion et al., 1997b; Czapla et al., 1998; Kwok and Dun, 1998; Makulska-Nowak et al., 2001), mice (Champion et al., 1998c), and rabbits (Champion et al., 1997a). Interestingly, both peptides produced dose-dependent biphasic changes in systemic arterial pressure in cats (Champion et al., 1998b). The cardiovascular responses to endomorphins were not altered by their repeated administration (Champion et al., 1999b). All of these effects were reversed by the µ-opioid receptor antagonists, naloxone and β-funaltrexamine, and were not blocked by the -or -opioid receptor antagonists, suggesting that the cardiovascular activity of endomorphins is primarily mediated by µ-opioid binding sites (Champion et al., 1998a; Czapla et al., 1998; Kwok and Dun, 1998; Makulska-Nowak et al., 2001). Surprisingly, the hypotensive effect of endomorphin-2 after i.c.v. administration in rats was less pronounced than that after i.v. injections (Czapla et al., 1998; Kwok and Dun, 1998; Makulska-Nowak et al., 2001). This suggests that the peripheral µ-opioid receptors might play an important role in the endomorphin-2-induced hypotensive effect (Rialas et al., 1998).

The mechanisms underlying the cardiovascular activity of endomorphins are not clear. It is commonly acknowledged that bradycardia is a consequence of vagus activation. Because atropine or bilateral vagotomy abolished the effects of endomorphin-1 on heart rate in rats, it was suggested that endomorphins might activate the vagal afferents. On the other hand, endomorphins are known to have inhibitory actions on neurons (Baraban and Stornetta, 1995; Hayar and Guyenet, 1998; Wu et al., 1999; Dun et al., 2000; Guyenet et al., 2002), and this effect is expected to elicit an increase in blood pressure and heart rate on the basis of known circuitry of cardiovascular regulatory areas in the medulla (Dampney, 1994; Sapru, 2002). Viard and Sapru (2006) demonstrated that microinjections of endomorphin-2, into the medial subnucleus of the NTS (mNTS) in rat attenuated reflex responses to stimulation of the carotid sinus and aortic baroreceptors. In this way both the inhibitory effect on the baroreflex and the excitatory effect on the mNTS neurons, resulting in depressor and bradycardic responses, were observed. The authors of this report hypothesized that the activity of the mNTS neurons might be under the dual control of the inhibitory influence of GABAergic neurons from the mNTS (Maqbool et al., 1991; Izzo and Sykes, 1992) and the excitatory influence of the glutamatergic projections from other areas of the brain, e.g., the insular cortex (Torrealba and Müller, 1996; Owens et al., 1999), to the mNTS (Fig. 8). The inhibitory effect of the GABA neurons in the mNTS (Fig. 8B) may be presynaptic (i.e., via inhibition of the release of Glu from the terminals) (Fig. 8C), as well as postsynaptic (i.e., via hyperpolarization of the postsynaptic neuron) (Fig. 8A). Inhibition of the GABAergic neurons by exogenously injected endomorphin-2 via the µ-opioid receptors located on the GABAergic neurons would result in increased release of Glu from presynaptic terminals, a reduction in the inhibitory influence on the postsynaptic neurons (disinhibition) and, in consequence, excitation of postsynaptic mNTS neurons. Endomorphin-2 might also act through the µ-opioid receptors located on the glutamatergic baroreceptor afferent terminals in response to baroreceptor stimulation (Fig. 8D), by decreasing Glu release and attenuating the baroreflex. All of these effects would explain the mechanism of the depressor and bradycardic responses to endomorphin-2 (Kasamatsu and Chitravanshi, 2004).

View larger version (21K): [in this window] [in a new window]   FIG. 8. Hypothetical model showing possible effects of exogenously administered endomorphin-2 in the mNTS. AMPA, -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid. Adapted from Brain Research, volume 1073–1074, Viard E and Sapru HN, "Endomorphin-2 in the Medial NTS Attenuates the Responses to Baroflex Activation," pages 365–373, copyright 2006, with permission from Elsevier.

13. Effects on Respiratory System. The opioid receptor ligands significantly influence the respiratory system (Bartho et al., 1987; Belvisi et al., 1990, 1992). In general, the opioid agonists produce respiratory depression (Haji et al., 2000), as it was observed for morphine (Kato, 1998; Takita et al., 1998; Weinger et al., 1998; Gwirtz et al., 1999; Mendelson et al., 1999; Osterlund et al., 1999; Sleigh, 1999; Czapla et al., 2000; Dershwitz et al., 2000; Heishman et al., 2000; Herschel et al., 2000; Hill and Zacny, 2000; Kishioka et al., 2000a,b; Krenn et al., 2000; Owen et al., 2000; Takita et al., 2000; Teppema et al., 2000), heroin (Vivian et al., 1998; Comer et al., 1999; Kishioka et al., 2000b), fentanyl (Gerak et al., 1998; Ma et al., 1998; Kishioka et al., 2000b), buprenorphine (Benedetti et al., 1999; Schuh et al., 1999), and DAMGO (Takita et al., 1998; Czapla et al., 2000), although some exceptions were reported (Greenwald et al., 1999; Mendelson et al., 1999; Angst et al., 2000; Czapla et al., 2000; Preston and Bigelow, 2000). Whereas numerous mechanisms are involved in respiratory regulation, the primary mechanism thought to be involved in opioid-induced respiratory depression is a general decrease in the sensitivity of brainstem respiratory centers to carbon dioxide, followed by a decrease in respiratory rate (for review, see Martin, 1983; Reisine and Pasternak, 1996; Shook et al., 1990).

Although endomorphin IR (Pierce and Wessendorf, 2000) and µ-opioid receptors (Moss, 2000; Moss and Laferriere, 2000) are colocalized in brain areas associated with respiratory control, such as the NTS and parabrachial nuclei (Martin-Schild et al., 1999), little is known about the effects of endomorphins on respiratory activity (Fig. 9). Intravenous injection of endomorphin-1 and endomorphin-2 at higher supra-analgesic doses produced biphasic effects in rats, characterized by an initial rapid ventilatory depression, lasting 4 to 6 s, followed by an increase in ventilation, lasting 10 to 12 min (Czapla et al., 2000). In contrast, morphine monotonically decreased ventilation. It is likely that the depressant activity of endomorphins was mediated by the central opioid receptors, because it was prevented by systemic injection of the centrally and peripherally acting opioid antagonist, naloxone, but not the peripherally restricted opioid antagonist, methylnaloxone (Czapla et al., 2000). In contrast, the excitatory effects of endomorphins were probably nonopioid-mediated, as they were not antagonized by typical opioid receptor antagonists.

View larger version (20K): [in this window] [in a new window]   FIG. 9. Hypothetical effects of endomorphins on the respiratory system.

Czapla and Zadina (2005) examined whether i.v. administered endomorphin-1 and endomorphin-2 affect the hypercapnic ventilatory response in rats and whether this modulation is mediated by a central mechanism. Endomorphins, in doses far higher than these corresponding to their analgesic threshold, depressed ventilation by attenuating the ventilatory response to hypercapnia. However, the threshold doses for respiratory depression were considerably higher for endomorphin-1 and endomorphin-2 than for DAMGO or morphine. To test whether modulation of the hypercapnic ventilatory responses were centrally mediated, endomorphin-1, endomorphin-2, DAMGO, and morphine were systemically administered before and after the i.v. administration of naloxone and methylnaloxone. The ventilatory effects of all µ-opioid agonists were blocked by naloxone, but not by methylnaloxone, thereby indicating a central action of the agonists on respiratory function. These results suggested that endomorphin-1 and endomorphin-2 produce weaker depression of the ventilatory response to hypercapnia than DAMGO or morphine. Differences in both pharmacokinetic factors, such as metabolic stability or penetration rate into the brain through the blood-brain barrier, and pharmacodynamic factors, such as receptor selectivity, agonist efficacy, or distinct cellular signaling could contribute to the observed dissimilarity among the µ-opioid receptor agonists. It is unclear, however, whether the opioids modulate the ventilatory response to hypercapnia by depressing neural function in chemosensitive neurons, in neurons associated with ventilatory rhythm generation, or in both.

The involvement of the nonopioid systems in endomorphin-induced effects on the respiratory activity was also studied. Fischer and Undem (1999) demonstrated that endomorphins produced a concentration-dependent inhibition of the electrical field stimulation-induced tachykinin-mediated contractions of the guinea pig bronchus. Surprisingly, only endomorphin-1 effects could be blocked by naloxone (10 µM), whereas endomorphin-2 effects were not affected by any opioid receptor-specific antagonist. Patel et al. (1999) showed that endomorphin-1 and endomorphin-2 gave a concentration-dependent and naloxone-sensitive inhibition of cholinergic contractile responses in guinea pig trachea. Both peptides also inhibited the electrically evoked ACh release from cholinergic nerves innervating guinea pig and human trachea. These results suggested that endomorphins can inhibit cholinergic, as well as nonadrenergic, noncholinergic (NANC) parasympathetic neurotransmission from postganglionic parasympathetic nerve fibers, which innervate airway smooth muscles, to the airways via the activation of classic opioid receptors (Belvisi et al., 1992). Different functional studies concluded that these effects are established via prejunctional µ-opioid receptors localized on both cholinergic and tachykinergic fiber types.

Recently, Asakawa et al. (2000) reported that endomorphins influenced oxidation processes. Intracerebroventricular injection of endomorphin-1 increased oxygen consumption in mice in a naloxone-reversible manner, indicating that this effect was mediated by the opioid receptors.

14. Effects on Gastrointestinal Tract. The effects of µ-opioid receptor ligands on the gastrointestinal tract are well established. Morphine inhibited gastrointestinal functions, transit and gastric emptying, in a naloxone-reversible manner (Asai, 1998; Asai et al., 1998). The µ-opioid receptor agonists were shown to influence small intestine motility both in vivo and in vitro (Puig et al., 1977; Nishiwaki et al., 1998; Allescher et al., 2000a), neurotransmitter release (Cosentino et al., 1997; Nishiwaki et al., 1998), and peristaltic reflex (Allescher et al., 2000a). Studies also revealed the fact that intestinal ascending contraction decreased via µ- and -receptors and latency increased via µ- and -opioid receptors (Olson et al., 1996; Allescher et al., 2000a,b). However, whereas opioid receptors present in the CNS have been thoroughly characterized, most groups failed to localize the µ-opioid receptor on the smooth muscle of the intestine, although different techniques, such as immunohistochemistry and receptor binding studies were used (Storr et al., 2002b). Grider and Makhlouf (1987) functionally characterized the µ-opioid receptor on the gut muscle layer, but because of the nerve/muscle preparation used, a neuronal effect could not have been excluded.

As expected, endomorphin-1 and endomorphin-2 also play important roles in the regulation of gastrointestinal functions. Tonini et al. (1998) analyzed the effects of endomorphin-1 and endomorphin-2, in a wide range of concentrations (3 x 10^-12 Mto10^-6 M), on ileum longitudinal muscle-myenteric plexus preparations from guinea pig ileum. Both peptides inhibited the amplitude of electrically induced twitch contractions in a concentration-dependent, CTOP-reversible manner, up to its abolition. Conversely, endomorphins failed to affect contractions to applied ACh on nonstimulated ileum longitudinal muscle-myenteric plexus preparations. These results demonstrated that endomorphins selectively activated µ-opioid receptors located on excitatory myenteric plexus neurons.

The effects of endomorphins on activity of smooth muscles in rat small intestine preparations were also characterized (Storr et al., 2002a). Both endomorphins inhibited the ascending contraction (i.e., attenuated the ascending excitatory reflex), increased the descending relaxation (stimulated the descending inhibitory reflex), and increased latency of onset of the contractile responses. Furthermore, endomorphin-1 and endomorphin-2 significantly reduced electrically induced smooth muscle twitch contractions. Inhibition of rat ileal smooth muscle activity was reversed by the µ-opioid receptor antagonist CTOP, confirming a specific µ-opioid receptor-mediated effect of endomorphins on the neural tissue in this preparation. Similar effects were observed for smooth and striated muscles of the rat esophagus (Storr et al., 2000a,b).

Endomorphins were shown to impair gastrointestinal transit by influencing various neural pathways. Yokotani and Osumi (1998) showed that endomorphin-1 and endomorphin-2 inhibited vagally evoked release of ACh from the isolated vascularly perfused rat stomach and suggested that the µ-opioid receptor is involved in this process. Cosentino et al. (1997) demonstrated that endomorphins modulated the adrenergic system by NA release in guinea pig colon. Storr et al. (2002a) suggested that endomorphins must act via µ-opioid receptors located on the presynaptic membrane of inhibitory NANC neurons and that they exert their effect on NANC relaxation by reducing release of the neurotransmitters involved (NO and vasoactive intestinal peptide). These effects could also be mediated by an inhibition of cholinergic nerve activity (Tonini et al., 1998; Yokotani and Osumi, 1998), which may indirectly result in an inhibition of NANC nerve activity.

B. Endomorphins, Neurotransmitters, and Neurohormones

In general, the exogenous and endogenous opioid receptor ligands elicit their biological effects by modifying the function of various neurotransmitter and neurohormone systems. Modulation of neurotransmitter release by opioids has been reviewed extensively (Illes, 1989; Jackisch, 1991; Mulder and Schoffelmeer, 1993). For example, it has been shown that opioids are able to influence the secretion of DA (Henderson et al., 1979; Iwamoto and Way, 1979; Vizi, 1979; Langer, 1981; De Vries et al., 1989; Mulder et al., 1989, 1991a,b; Chen et al., 2001; Ukai and Lin, 2002a; Bujdoso et al., 2003; Huang et al., 2004), NA (Starke, 1977; Westfall, 1977; Henderson et al., 1979; Iwamoto and Way, 1979; Vizi, 1979; Langer, 1981; Szekely and Ronai, 1982a,b; Hagan and Hughes, 1984; Chen et al., 2001; Al-Khrasani et al., 2003; Hung et al., 2003), 5-HT (Hagan and Hughes, 1984; Passarelli and Costa, 1989; Wichmann et al., 1989; Mulder and Schoffelmeer, 1993; Chen et al., 2001), and ACh (Domino, 1979; Jhamandas and Sutak, 1980). Moreover, opioids may also alter the release of various neurohormones (Szekely and Ronai, 1982b; Pfeiffer and Herz, 1984; Millan and Herz, 1985; Tuomisto and Männistö, 1985; Howlett and Rees, 1986).

In the last part of this review, the relationship between endomorphins and neurotransmitter and neurohormone systems is briefly summarized.

1. Modulation of Dopamine Transmission. The µ-opioid receptors are found in high density in dopaminergic pathways in the Nac and corpus striatum (Khachaturian et al., 1985; Fallon and Leslie, 1986; Eghbali et al., 1987; Mansour et al., 1988) and seem to play an important role in dopaminergic transmission in both structures. Activation of µ-opioid receptors in the Nac is known to increase accumbal DA release or DA efflux in rats (Spanagel et al., 1992). Okutsu et al. (2006) studied the ability of endomorphins to alter the accumbal extracellular DA level by means of microdialysis in freely moving rats. Infusion of endomorphin-1 or endomorphin-2 into the Nac produced a dose-dependent increase of the accumbal DA level. Endomorphin-1-induced DA efflux was abolished by intraccumbal perfusion of CTOP, systemic administration of naloxone, and systemic administration of the µ₁-receptor antagonist naloxonazine. The µ-receptor antagonists failed to affect endomorphin-2-induced DA efflux, suggesting that the effects produced by endomorphin-2 are not mediated by µ-opioid receptors. This result is in good agreement with those of earlier reports, showing that the ability of endomorphin-2 to stimulate the release of DA in the Nac and to increase the level of DA metabolites, DOPAC and HVA, in the shell of the Nac, resulted from activation of the mesolimbic system and disinhibition of the local GABA neurons (Johnson and North, 1992; Huang et al., 2004).

In the striatum, opioids act predominantly at the presynaptic opioid receptors and produce different indirect effects on DA turnover, depending on the receptor type (Clouet and Ratner, 1970; Smith et al., 1972; Gauchy et al., 1973). Locally administered µ-opioid agonists were shown to increase DA efflux through postsynaptic µ-opioid receptors (Dourmap et al., 1992). This efflux was not accompanied, however, by modification of DA uptake or an increase in the level of two main DA metabolites, DOPAC and HVA (Das et al., 1994). Dourmap et al. (1997) showed that modulation of DA release by µ-opioid receptors required the integrity of cholinergic and, to a lesser level, of GABAergic neurons in the striatum. The µ-opioid agonists applied to the striatum might also act at presynaptic sites on nigrostriatal DA neurons, activating DA receptors to prevent DA release.

In the study of Yonehara and Clouet (1984), the levels of DA and its catabolites after intracisternal administration of morphiceptin in rat were measured. Morphiceptin produced a decrease in the levels of 3-methoxytyramine, suggesting an inhibition of DA release (Das et al., 1994). However, no such studies were performed for other µ-opioid receptor-selective ligands, including endomorphins.

2. Modulation of Noradrenaline Transmission. The LC consists of a compact group of NA-containing cell bodies close to the floor of the fourth ventricle at the upper border of pons (Nestler et al., 1994). LC innervates all levels of the neuraxis and can simultaneously influence functionally diverse neural targets (Waterhouse et al., 1983, 1993; Simpson et al., 1997). It is the primary source of NA in the forebrain and the sole source of NA in the cortex and hippocampus (Aston-Jones et al., 1985; Lewis et al., 1987; McCormick et al., 1991). LC is the primary origin of descending noradrenergic analgesic fibers (Proudfit, 1988; Jones, 1991; Lipp, 1991). Electrophysiological studies and microscopic autoradiography revealed a high µ-opioid receptor density in the LC (Mansour et al., 1986, 1995).

Yang et al. (1999) investigated the influence of natural and synthetic µ-opioid selective peptides (morphiceptin, hemorphin-4, Tyr-MIF-1, Tyr-W-MIF-1, endomorphins, Tyr-D-Arg-Phe-Sar, and Tyr-D-Arg-Phe-Lys-NH₂) on the activity of the LC using intracellular recording techniques. All peptides tested reduced the excitability of LC neurons in a concentration-dependent, D-Phe-c(Cys-Tyr-D-Trp-Arg-Thr-Pen)-Thr-NH₂-reversible manner. They inhibited spontaneous firing, induced the hyperpolarization of the membrane potential by opening inward-going rectification potassium channels, and reduced the neuronal input resistance. Endomorphin-1 and endomorphin-2, which were the most effective endogenous opioid peptides, were almost equipotent, and their electrophysiological effects on LC neurons showed similar amplitude and time course. Furthermore, the concentrations of endomorphins required to elicit hyperpolarization of the membrane potential were much lower than those for other opioids, including morphine, β-endorphin, and DAMGO. The authors of the study speculated that the presence of an aromatic group in position 4 and the amidation of the C terminus in endomorphins are crucial both for high µ-receptor binding affinity and a significant electrophysiological response of LC neurons.

Peoples et al. (2002) examined the ultrastructural associations of endomorphin-1 with the NA neurons of the LC and the peptidergic neurons of Barrington's nucleus in the brainstem dorsal pontine tegmentum. Both structures, targeted by endogenous opioids (Sutin and Jacobowitz, 1988; Van Bockstaele et al., 1996c) and enriched with µ-opioid receptors (Atweh and Kuhar, 1977; Van Bockstaele et al., 1996a,b), might be involved in the reduction of the excitability of the LC neurons caused by endomorphins (Peoples et al., 2002). It was demonstrated that endomorphin-1-immunoreactive axon terminals form synaptic specializations with tyrosine hydroxylase- and CRF-containing dendrites in peri-LC and Barrington's nucleus, respectively, in the dorsal pontine tegmentum of the rat brain. Endomorphin-1 could modulate the LC neurons directly in this structure by tonically inhibiting the neurons in the Barrington's nucleus.

The potential interactions between endomorphin-1 and NA transmission in the spinal cord have also been studied (Hao et al., 2000). Intrathecally administered endomorphin-1 in rats activated local NA terminals and stimulated the release of NA in the spinal cord. Thus, the peptide indirectly activated ₂-receptors and produced analgesia in rats, as measured in the tail-flick, tail pressure, and formalin tests.

3. Modulation of Serotonin Transmission. Serotoninergic transmission is important in various physiological processes, especially nociception (Driessen and Reimann, 1992; Pini et al., 1997), stress and anxiety (Petty et al., 1992; Kawahara et al., 1993), and food intake (Kaye, 1997; Mercer and Holder, 1997), in which the opioid system has also been implicated. The largest population of serotoninergic cell bodies is located within the ventral portion of the PAG, in the dorsal raphe nucleus (DRN), an area involved in the integration of the responses to stress (Basbaum and Fields, 1984; Roche et al., 2003). Pain and stressful stimuli activate opioidergic neurons in the PAG, which in turn modulate the activity of serotoninergic neurons with projections to the sites involved in emotional states (Ma and Han, 1992; Grahn et al., 1999).

The extracellular level of 5-HT in DRN can be used as an indicator of neuronal activity and serotonin release in the forebrain (Tao and Auerbach, 1995). Electrophysiological studies showed that µ-opioids have inhibitory effects on serotoninergic neuronal discharge in the DRN (Haigler, 1978; North, 1986), whereas the in vivo microdialysis with µ-opioids stimulated serotoninergic activity (Tao and Auerbach, 1995; Kalyuzhny et al., 1996). This inconsistency could be explained by the interaction of the opioidergic and serotoninergic systems in the DRN. The µ-opioid receptor-containing synaptic endings are present in the DRN (Wang and Nakai, 1994), but the opioid agonists do not excite 5-HT neurons directly (Tao and Auerbach, 1995; Jolas and Aghajanian, 1997). The µ-opioid-induced change in 5-HT efflux represents a balance between two competing effects, inhibition of endogenous GABAergic afferents and disinhibition of 5-HT neurons by enhancing the excitatory influence of Glu, which is attenuated by direct inhibition of glutamatergic afferents (Tao et al., 1996; Jolas and Aghajanian, 1997; Kalyuzhny and Wessendorf, 1997; Gervasoni et al., 2000). Although the net effect depends on the initial equilibrium between GABAergic (inhibitory) and glutamatergic (excitatory) influences on 5-HT neurons, the µ-opioids seem to favor the increase in extracellular 5-HT.

The effect of in vivo microdialysis with endomorphin-1 and endomorphin-2 on extracellular levels of 5-HT in the rat DRN has been investigated (Tao and Auerbach, 2002). Both peptides increased the efflux and the extracellular level of 5-HT in the DRN. Endomorphins produced a shorter-lasting and, in the case of endomorphin-2, a lower response than DAMGO, which could be due to a faster rate of degradation of those peptides. The response was blocked by a selective µ-opioid receptor antagonist, β-funaltrexamine.

The influence of endomorphins on 5-HT levels in other brain areas has also been studied. Endomorphins injected into the VTA reduced serotoninergic activity in the medial prefrontal cortex and ventral striatum (Chen et al., 2001), which might suggest that they stimulate µ-opioid receptors and might mediate the depletion of 5-HT in both brain regions. As shown by Huang et al. (2004), both endomorphins showed no effect on the serotonin metabolite, 5-hydroxyindoleacetic acid in the Nac.

In the neocortex, endomorphin-1 produced a naloxone-reversible inhibitory effect on K⁺-stimulated 5-HT overflow (Sbrenna et al., 2000). This observation clearly indicated that in the neocortex µ-opioid receptors are located on serotoninergic nerve terminals and suggested a direct presynaptic modulation of serotoninergic terminals by µ-receptors in this brain area.

In the medial prefrontal cortex, DAMGO and endomorphin-1 produced a strong, CTOP-reversible suppression of the 5-HT_2A-induced excitatory postsynaptic currents in layer V pyramidal cells (Marek and Aghajanian, 1998). It was also demonstrated that the µ-opioid receptor agonists acted on neuronal elements presynaptically to the pyramidal cells. It was proposed that 5-HT_2A and the µ-receptor ligands interact physiologically on a subset of glutamatergic afferents to medial prefrontal cortical layer V pyramidal cells and the apparent neocortical source for both receptor types might be layer VI pyramidal cells (Vogt et al., 1995). A subcortical candidate for this unique population of afferents might be the thalamus or basolateral nucleus of the amygdala (Krettek and Price, 1977; Delfs et al., 1994; Mansour et al., 1994; Bacon et al., 1996). It was concluded that the physiological interaction between 5-HT_2A and µ-receptors in the CNS may be of substantial importance, given the heavy and widespread cortical localization of both receptor types.

4. Modulation of Acetylcholine Transmission. As discussed in detail above (sections VI.A.11., VI.A.13., and VI.A.14.), endomorphins may modulate cholinergic neurotransmission in peripheral tissues, mainly in the respiratory system and the gastrointestinal tract. They are believed to exert these inhibitory effects by acting through prejunctional µ-opioid receptors to inhibit release of contractile transmitters.

Evidence for the possible role of endomorphin-1 in the regulation of cholinergic neurotransmission in the inner ear has also been reported. Lioudyno et al. (2002) investigated the ability of endomorphin-1 to modulate ACh-evoked currents in isolated frog saccular hair cells and rat inner hair cells by means of the patch-clamp recording method. They observed that endomorphin-1 inhibited ACh-evoked currents and suggested that endomorphins may interact with nicotinic acetylcholine receptors.

5. Modulation of Neurohormone Release. Oxytocin (OT) and AVP are neurohormones synthesized by magnocellular neurosecretory cells in the PVN and supraoptic nucleus (SON) of the hypothalamus. The PVN and SON project to the posterior pituitary, where OT and AVP are secreted directly into the systemic circulation (Hatton, 1990). In vivo studies demonstrated that the opioid systems participate in regulation of the electrical activity of the OT and AVP neurons and the release of both hormones (Russell et al., 1995; Brown and Leng, 2000). The µ-opioid receptor agonists decreased the basal levels of both OT (Clarke et al., 1979; Frederickson et al., 1981; Clarke and Patrick, 1983; Hartman et al., 1987) and AVP (Van Wimersma Greidanus et al., 1979; Aziz et al., 1981). However, more recent studies showed that the µ-opioid receptor agonists inhibited only OT cells, whereas the activity of AVP neurons was diminished exclusively by -opioid receptor agonists (Pumford et al., 1993).

The only report on the association of endomorphins and the level of both neurohormones was published by Doi et al. (2001), showing that i.c.v. administered endomorphin-1 in rats inhibited both OT and AVP SON cells, but in a different manner. The OT cells were much more sensitive to endomorphin-1-induced inhibition than the AVP cells, which may suggest that they express µ-opioid receptors at a much higher level.

Several studies have demonstrated that i.c.v. (Liu et al., 2002), i.p. (Agren et al., 1997), and intracisternal administration of OT (Arletti et al., 1993), as well as direct injections of OT to the PAG (Zhang et al., 2000) and the nucleus raphe magnus (Robinson et al., 2002), induced antinociceptive effects in animals and humans (Arletti et al., 1993; Lundeberg et al., 1994; Louvel et al., 1996; Petersson et al., 1996; Agren et al., 1997; Caron et al., 1998; Kang and Park, 2000). The involvement of opioid receptors in OT-induced antinociception in the CNS has also been investigated (Wang et al., 2003; Zubrzycka et al., 2005). The OT-induced antinociceptive effects to both thermal and mechanical stimulation in rats were blocked significantly by i.c.v. administration of β-FNA, indicating that µ-opioid receptors are involved. Unfortunately, so far there are no data on the involvement of endogenous µ-opioid receptor ligands, endomorphins, in OT-induced antinociception.

Likewise, the relationship between endomorphins and AVP needs to be elucidated. Recent evidence suggested that the increased vasopressinergic neuronal activity in the amygdala or hypothalamus represents an important step in the neurobiology of stress-related behaviors. For example, acute stress increased extracellular levels of AVP in the rat amygdala or hypothalamus (Ebner et al., 2002; Wigger et al., 2004) and the activation of V1 receptors by AVP may underlie anxiogenic and depressive behaviors in the rat (Liebsch et al., 1996; Griebel et al., 2002; Wigger et al., 2004). These data suggest that further studies with endomorphins are needed.

A potential role of µ-opioid receptors for regulatory processes in the stomach is supported by autoradiographic (Nishimura et al., 1984, 1986), immunohistochemical (Fickel et al., 1997), and physiological (McIntosh et al., 1990) investigations. Lippl et al. (2001) examined the effects of endomorphins on gastric neuroendocrine functions. Endomorphin-1 has been shown to inhibit somatostatin stimulation in the perfused rat stomach. Blockade of µ-opioid receptors with CTOP, a selective µ-opioid receptor antagonist, significantly, but not completely, antagonized the inhibitory effect of endomorphin-1. These results suggest that the inhibitory effect of endomorphin-1 on somatostatin activity is mediated in large part by µ-opioid receptors.

	VII. Conclusions

Top Previous Next

 
Since their discovery in 1970s, the opioid peptides have become increasingly important in our understanding of brain functions. Endomorphin-1 and endomorphin-2, isolated from mammalian brain nearly a decade ago, are endogenous opioid peptides with high affinity and extreme selectivity for the µ-opioid receptors. Endomorphins and the µ-opioid receptors display widespread localization in the central and peripheral nervous systems and seem to participate in many distinct neuronal circuits, thereby exerting a multitude of diverse functions in a variety of animal species. As matter of fact, endomorphins have been implicated in a broad range of biological processes, including nociception, cardiovascular, respiratory, feeding, and digestive functions, responses related to stress, and complex functions such as reward, arousal, and vigilance, as well as autonomic, cognitive, endocrine, and limbic homeostasis. Whether these activities reflect direct or indirect responses to endomorphins remains a matter of speculation. To answer this fundamental question, the elucidation of endomorphin synthesis and degradation pathways, the recognition of exact mechanisms of action, and the identification of the principal pathways involved in their effects are obviously required. Other important issues, such as the complex relationship with neurotransmitters and neurohormones, also need to be clarified.

The beneficial effects of endomorphins in various pathological conditions such as pain, mood, and feeding disorders, related to reward and cardiorespiratory function, will undoubtedly motivate the development of new ligands. These ligands would preferably be endomorphinomimetics with high µ-opioid receptor affinity and good resistance to proteolytic degradation, which could potentially be used as analgesic, anxiolytic or antidepressant agents.

	Acknowledgements

 
We thank Dr. Jean-Luc do Rego for excellent help and advice with the preparation of this manuscript.

	Footnotes

 
Address correspondence to: Dr. Jean-Claude do Rego, Laboratory of Experimental Neuropsychopharmacology, CNRS FRE 2735, IFRMP 23, Faculty of Medicine & Pharmacy, University of Rouen, 22, Boulevard Gambetta, 76183 Rouen cedex, France. E-mail: jean-claude.dorego{at}univ-rouen.fr

This work was supported by grants from the Conseil Régional de Haute Normandie (to J.F.), a grant "Start" from the Foundation for Polish Science (to J.F.), grants from the Medical University of Lodz (502-11-460 and 502-11-461), and by the Centre National de la Recherche Scientifique (Paris, France).

This article is available online at http://pharmrev.aspetjournals.org.

doi:10.1124/pr.59.1.3.

¹ Abbreviations: Tyr-MIF, Tyr-Pro-Leu-Gly-NH₂; Tyr-W-MIF, Tyr-Pro-Trp-Gly-NH₂; IR, immunoreactivity; CNS, central nervous system; PAG, periaqueductal gray; LC, locus coeruleus; NTS, nucleus of the solitary tract; Nac, nucleus accumbens; VTA, ventral tegmental area; DAMGO, Tyr-D-Ala-Gly-MePhe-Gly-ol; i.c.v., intracerebroventricular; i.t., intrathecal; ACh, acetylcholine; DPP IV, dipeptidyl-peptidase IV; Glu, glutamate; 5-HT, serotonin; NA, noradrenalin; 6-OHDA, 6-hydroxydopamine; 5,7-DHT, 5,7-dihydroxytryptamine; DA, dopamine; NO, nitric oxide; CTOP, D-Phe-c(Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂); HPA, hypothalamo-pituitary-adrenal; CRF, corticotrophin-releasing factor; AVP, arginine vasopressin; ACTH, adrenocorticotropin; FST, forced swimming test; BDNF, brain-derived neurotrophic factor; VMH, ventromedial hypothalamus; mPOA, medial preoptic area; MCG, mesencephalic central gray; MS-HDB, medial septum-horizontal limb of the diagonal band; PVN, paraventricular nucleus; mNTS, medial subnucleus of the nucleus of the solitary tract; NANC, nonadrenergic, noncholinergic; DRN, dorsal raphe nucleus; OT, oxytocin.

	References

Top

 

Acosta-Martinez M and Etgen AM (2002) Activation of µ-opioid receptors inhibits lordosis behavior in estrogen and progesterone-primed female rats. Horm Behav 41: 88-100.[CrossRef][Medline]

Agren G, Uvnas-Moberg K, and Lundeberg T (1997) Olfactory cues from an oxytocin-injected male rat can induce anti-nociception in its cage-mates. NeuroReport 8: 3073-3076.[Medline]

Aguilar MA, Minarro J, and Simoon VM (1998) Dose-dependent impairing effects of morphine on avoidance acquisition and performance in male mice. Neurobiol Learn Mem 69: 92-105.[CrossRef][Medline]

Aimone LD and Gebhart GF (1986) Stimulation-produced spinal inhibition from the midbrain in the rat is mediated by an excitatory amino acid transmitter in the medial medulla. J Neurosci 6: 1803-1813.[Abstract]

Albin RL, Qin Y, Young AB, Penney JB, and Chesselet M-F (1991) Preproenkephalin messenger RNA-containing neurons in striatum of patients with symptomatic and presymptomatic Huntington's disease: an in situ hybridization study. Ann Neurol 30: 542-549.[CrossRef][Medline]

Albonetti ME and Farabollini F (1994) Social stress by repeated defeat: effects on social behaviour and emotionality. Behav Brain Res 62: 187-193.[CrossRef][Medline]

Al-Khrasani M, Elor G, Abbas MY, and Ronai AZ (2003) The effect of endomorphins on the release of ³H-norepinephrine from rat nucleus tractus solitarii slices. Regul Pept 111: 97-101.[CrossRef][Medline]

Allescher HD, Storr M, Brechmann C, Hahn A, and Schusdziarra V (2000a) Modulatory effect of endogenous and exogenous opioids on the excitatory reflex pathway of the rat ileum. Neuropeptides 34: 62-68.[CrossRef][Medline]

Allescher HD, Storr M, Piller C, Brantl V, and Schusdziarra V (2000b) Effect of opioid active therapeutics on the ascending reflex pathway in the rat ileum. Neuropeptides 34: 181-186.[CrossRef][Medline]

Alt A, Mansour A, Akil H, Medzihradsky F, Traynor JR, and Woods JH (1998) Stimulation of guanosine-5'-O-(3-[³⁵S]thio)triphosphate binding by endogenous opioids acting at a cloned mu receptor. J Pharmacol Exp Ther 286: 282-288.[Abstract/Free Full Text]

Amiche M, Sagan S, Mor A, Delfour A, and Nicolas P (1989) Dermenkephalin (Tyr-D-Met-Phe-His-Leu-Met-Asp-NH₂): a potent and fully specific agonist for the delta opioid receptor. Mol Pharmacol 35: 774-779.[Abstract]

Anagnostakis Y, Kribos Y, and Spyraki C (1992) Pallidal substrate of morphine-induced locomotion. Eur Neuropsychopharmacol 2: 65-72.[CrossRef][Medline]

Andrade ML, Kamal KBH, and Brain PF (1989) Effects of positive and negative fighting experiences in behavior on adult male mice, in House Mouse Aggression: a Model for Understanding the Evolution of Social Behaviour (Brain PF, Maimdardi D and Parmigiani S eds) pp 223-232 Harwood Academic, Chur, Switzerland.

Angst MS, Ramaswamy B, Riley ET, and Stanski DR (2000) Lumbar epidural morphine in humans and supraspinal analgesia to experimental heat pain. Anesthesiology 92: 312-324.[CrossRef][Medline]

Argiolas A (1999) Neuropeptides and sexual behaviour. Neurosci Biobehav Rev 23: 1127-1142.[CrossRef][Medline]

Arletti R, Benelli A, and Bertolini A (1993) Influence of oxytocin on nociception and morphine antinociception. Neuropeptides 24: 125-129.[CrossRef][Medline]

Asai T (1998) Effects of morphine, nalbuphine and pentazocine on gastric emptying of indigestible solids. Drug Res 48: 802-805.[Medline]

Asai T, Mapleson WW, and Power I (1998) Effects of nalbuphine, pentazocine and U50488H on gastric emptying and gastrointestinal transit in the rat. Br J Anaesth 80: 814-819.[Abstract/Free Full Text]

Asakawa A, Inui A, Momose K, Ueno N, Fujino MA, and Kasuga M (1998) Endomorphins have orexigenic and anxiolytic activities in mice. NeuroReport 9: 2265-2267.[Medline]

Asakawa A, Inui A, Ueno N, Fujimiya M, Fujino MA, and Kasuga M (2000) Endomorphin-1, an endogenous µ-opioid receptor-selective agonist, stimulates oxygen consumption in mice. Horm Metab Res 32: 51-52.[Medline]

Aston-Jones G, Foote SL, and Segal M (1985) Impulse conduction properties of noradrenergic locus coeruleus axons projecting to monkey cerebrocortex. Neuroscience 15: 765-777.[CrossRef][Medline]

Atweh SF and Kuhar MJ (1977) Autoradiographic localization of opiate receptors in rat brain. II. The brain stem. Brain Res 129: 1-12.[CrossRef][Medline]

Austin MC and Kalivas PW (1990) Enkephalinergic and GABAergic modulation of motor activity in the ventral pallidum. J Pharmacol Exp Ther 252: 1370-1377.[Abstract/Free Full Text]

Avgustinovich DF, Gorbach OV, and Kudryavtseva NN (1996) Comparative analysis of anxiety-like behavior in partition and plus-maze tests after agonistic interactions in mice, Physiol Behav 61: 37-43.

Aziz L, Forsling ML, and Woolf CJ (1981) The effect of intracerebroventricular injections of morphine on vasopressin release in the rat. J Physiol (Lond) 311: 401-409.[Abstract/Free Full Text]

Babbini M and Davis WM (1972) Time-dose relationship for locomotor activity effects of morphine after acute or repeated treatment. Br J Pharmacol 46: 213-224.[Medline]

Bacon SJ, Headlam AJ, Gabbott PL, and Smith AD (1996) Amygdala input to medial prefrontal cortex (mPFC) in the rat: a light and electron microscope study. Brain Res 720: 211-219.[CrossRef][Medline]

Bairoch A (1996) The ENZYME data bank in 1995. Nucleic Acids Res 24: 221-222.[Abstract/Free Full Text]

Bakker J and Baum MJ (2000) Neuroendocrine regulation of GnRH release in induced ovulators. Front Neuroendocrinol 21: 220-262.[CrossRef][Medline]

Baraban SC and Stornetta RL (1995) Effects of morphine and morphine withdrawal on adrenergic neurons of the rat rostral ventrolateral medulla. Brain Res 676: 245-257.[CrossRef][Medline]

Barr GA and Zadina JE (2000) The ontogeny of endomorphin-1- and endomorphin-2-like immunoreactivity in rat brain and spinal cord. Ann NY Acad Sci 897: 145-153.[CrossRef]

Bartho L, Amann R, Saria A, Szolcsanyi J, and Lembeck F (1987) Peripheral effects of opioid drugs on capsaicin-sensitive neurones of the guinea-pig bronchus and rabbit ear. Naunyn-Schmiedeberg's Arch Pharmacol 336: 316-320.[Medline]

Basbaum AI and Fields HL (1984) Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 7: 309-338.[CrossRef][Medline]

Baumann MH, Elmer GI, Goldberg SR, and Ambrosio E (2000) Differential neuroendocrine responsiveness to morphine in Lewis, Fischer 344, and ACI inbred rats. Brain Res 858: 320-326.[CrossRef][Medline]

Becker A, Grecksch G, Brodemann R, Kraus J, Peters B, Schroeder H, Thiemann W, Loh HH, and Hollt V (2000) Morphine self-administration in µ-opioid receptor-deficient mice. Naunyn-Schmiedeberg's Arch Pharmacol 361: 584-589.[CrossRef][Medline]

Belenky G and Holaday JW (1979) The opiate antagonist naloxone modifies the effects of electroconvulsive shock (ECS) on respiration, blood pressure and heart rate. Brain Res 177: 414-417.[CrossRef][Medline]

Belluzzi JD and Stein L (1977) Enkephaline may mediate euphoria and drive-reduction reward. Nature (Lond) 266: 556-558.[CrossRef][Medline]

Belvisi MG, Stretton CD, and Barnes PJ (1990) Modulation of cholinergic neurotransmission in guinea-pig airways by opioids. Br J Pharmacol 100: 131-137.[Medline]

Belvisi MG, Stretton CD, Verleden GM, Ledingham SJ, Yacoub MH, and Barnes PJ (1992) Inhibition of cholinergic neurotransmission in human airways by opioids. J Appl Physiol 72: 1096-1100.[Abstract/Free Full Text]

Benedetti F, Amanzio M, Baldi S, Casadio C, and Maggi G (1999) Inducing placebo respiratory depressant responses in humans via opioid receptors. Eur J Neurosci 11: 625-631.[CrossRef][Medline]

Bernard JF, Huang GF, and Besson JM (1992) Nucleus centralis of the amygdala and the globus pallidus ventralis: electrophysiological evidence for an involvement in pain processes. J Neurophysiol 68: 551-569.[Abstract/Free Full Text]

Berne PF, Schmitter JM, and Blanquet S (1990) Peptide and protein carboxylterminal labeling through carboxypeptidase Y-catalyzed transpeptidation. J Biol Chem 265: 19551-19559.[Abstract/Free Full Text]

Besson A, Privat AM, Eschalier A, and Fialip J (1996) Effects of morphine, naloxone and their interaction in the learned helplessness paradigm in rats. Psychopharmacology (Berl) 123: 71-78.[CrossRef][Medline]

Binder DK and Scharfman HE (2004) Brain-derived neurotrophic factor. Growth Factors 22: 123-131.[CrossRef][Medline]

Blanchard RJ, Herbert M, Sakai RR, McKittrick C, Henrie A, Yudko E, McEwen B, and Blanchard DC (1998a) Chronic social stress: changes in behavioral and physiological indices of emotion. Aggress Behav 24: 307-321.[CrossRef]

Blanchard RJ, Nikulina JN, Sakai RR, McKittrick C, McEwen B, and Blanchard DC (1998b) Behavioral and endocrine change following chronic predatory stress. Physiol Behav 63: 561-569.[CrossRef][Medline]

Blanchard SG, Lee PHK, Pugh WW, Hong JS, and Chang KJ (1987) Characterization of the binding of a morphine (mu) receptor-specific ligand: Tyr-Pro-NMePhe-D-Pro-NH₂, [³H]-PL17. Mol Pharmacol 31: 326-333.[Abstract]

Bloom FE (1983) The endorphins: a growing family of pharmacologically pertinent peptides. Annu Rev Pharmacol Toxicol 23: 151-170.[CrossRef][Medline]

Bodkin JA, Zornberg GL, Lukas SE, and Cole JO (1995) Buprenorphine treatment of refractory depression. J Clin Psychopharmacol 15: 49-57.[CrossRef][Medline]

Bodnar RJ and Klein GE (2004) Endogenous opiates and behavior: 2003. Peptides 25: 2205-2256.[CrossRef][Medline]

Bohm S, Grady EF, and Bunnett NW (1997) Mechanisms attenuating signaling by G protein-coupled receptors. Biochem J 322: 1-18.[Medline]

Bohus B, Koolhaas JM, and Korte SM (1990) Psychosocial stress, anxiety, and depression: physiological and neuroendocrine correlated in animal models, in Stress and Related Disorders from Adaptation to Dysfunction (Genazzani AR, Nappi G, Petraglia F, Martignoni E eds) Parthenon, Pearl City, NY.

Boscan P, Pickering AE, and Paton JFR (2002) The nucleus of the solitary tract: an integrating station for nociceptive and cardiorespiratory afferents. Exp Physiol 87: 259-266.[Abstract]

Bostock E, Gallagher M, and King RA (1988) Effects of opioid microinjections into the medial septal area on spatial memory in rats. Behav Neurosci 102: 643-652.[CrossRef][Medline]

Bourin M (1990) Is it possible to predict the activity of a new antidepressant in animals with simple psychopharmacological tests? Fundam Clin Pharmacol 4: 49-64.[Medline]

Bozu B, Fulop F, Toth GK, Toth G, and Szucs M (1997) Synthesis and opioid binding activity of dermorphin analogues containing cyclic β-amino acids. Neuropeptides 31: 367-372.[CrossRef][Medline]

Brandao ML, Anseloni VZ, Pandossio JE, De Araujo JE, and Castilho VM (1999) Neurochemical mechanisms of the defensive behavior in the dorsal midbrain. Neurosci Biobehav Rev 23: 863-875.[CrossRef][Medline]

Brantl V, Gramsch C, Lottspeich F, Mertz R, Jaeger K-H, and Herz A (1986) Novel opioid peptides derived from hemoglobin: hemorphins. Eur J Pharmacol 125: 309-310.[CrossRef][Medline]

Broderick PA (1985) In vivo electrochemical studies of rat striatal dopamine and serotonin release after morphine. Life Sci 36: 2269-2275.[CrossRef][Medline]

Brown CH and Leng G (2000) In vivo modulation of post-spike excitability in vasopressin cells by -opioid receptor activation. J Neuroendocrinol 12: 711-714.[CrossRef][Medline]

Buccafusco JJ, Zhang LC, Shuster LC, Jonnala RR, and Gattu M (2000) Prevention of precipitated withdrawal symptoms by activating central cholinergic systems during a dependence-producing schedule of morphine in rats. Brain Res 852: 76-83.[CrossRef][Medline]

Bujdoso E, Jaszberenyi M, Gardi J, Foldesic I, and Telegdy G (2003) The involvement of dopamine and nitric oxide in the endocrine and behavioural action of endomorphin-1. Neuroscience 120: 261-268.[CrossRef][Medline]

Bujdoso E, Jaszberenyi M, Tomboly C, Toth G, and Telegdy G (2001) Behavioral and neuroendocrine actions of endomorphin-2. Peptides 22: 1459-1463.[CrossRef][Medline]

Byck R (1976) Peptide transmitters: a unifying hypothesis for euphoria, respiration, sleep, and the action of lithium. Lancet 2: 72-73.[Medline]

Calenco-Choukroun G, Dauge V, Gacel G, Feger J, and Roques BP (1991) Opioid delta agonists and endogenous enkephalins induce different emotional reactivity than mu agonists after injection in the rat ventral tegmental area. Psychopharmacology (Berl) 103: 493-502.[CrossRef][Medline]

Calignano A, Persico P, Mancuso F, and Sorrentino L (1993) L-Arginine modulates morphine-induced changes in locomotion in mice. Ann 1st Super Sanita 29: 409-412.

Caron RW, Leng G, Ludwig M, and Russell JA (1998) Naloxone-induced supersensitivity of oxytocin neurones to opioid antagonists. Neuropharmacology 37: 887-897.[CrossRef][Medline]

Castellano C, Cestari V, Cabib S, and Puglisi-Allegra S (1994) The effects of morphine on memory consolidation in mice involve both D1 and D2 dopamine receptors. Behav Neural Biol 61: 156-161.[CrossRef][Medline]

Castren E (2004) Neurotrophins as mediators of drug effects on mood, addiction, and neuroprotection. Mol Neurobiol 29: 289-302.[CrossRef][Medline]

Champion HC, Bivalacqua TJ, Friedman DE, Zadina JE, Kastin AJ, and Kadowitz PJ (1998a) Nitric oxide release mediates vasodilator responses to endomorphin 1 but not nociceptin/OFQ in the hindquarters vascular bed of the rat. Peptides 19: 1595-1602.[CrossRef][Medline]

Champion HC, Bivalacqua TJ, Lambert DG, McWilliams SM, Zadina JE, Kastin AJ, and Kadowitz PJ (1998b) Endomorphin 1 and 2, the endogenous µ-opioid agonists, produce biphasic changes in systemic arterial pressure in the cat. Life Sci 63: PL131-PL136.[CrossRef][Medline]

Champion HC, Bivalacqua TJ, Zadina JE, Kastin AJ, and Kadowitz PJ (1999a) Vasodilator responses to the endomorphin peptides, but not nociceptin/OFQ, are mediated by nitric oxide release. Ann NY Acad Sci 897: 165-172.[CrossRef][Medline]

Champion HC, Bivalacqua TJ, Zadina JE, Kastin AJ, Hyman AL, and Kadowitz PJ (2002) Role of nitric oxide in mediating vasodilator responses to opioid peptides in the rat. Clin Exp Pharmacol Physiol 29: 229-232.[CrossRef][Medline]

Champion HC and Kadowitz PJ (1998) D-[Ala²-endomorphin 2 and endomorphin 2 have nitric oxide-dependent vasodilator activity in rats. Am J Physiol 274: H1690-H1697.[Medline]

Champion HC, Zadina JE, Kastin AJ, Hackler L, Ge L-J, and Kadowitz PJ (1999b) Endomorphin 1 and 2, endogenous ligands for the µ-opioid receptor, decrease cardiac output, and total peripheral resistance in the rat. Peptides 18: 1393-1397.[CrossRef]

Champion HC, Zadina JE, Kastin AJ, Hackler L, Ge L-J, and Kadowitz PJ (1997a) The endogenous µ-opioid receptor agonists endomorphins 1 and 2 have novel hypotensive activity in the rabbit. Biochem Biophys Res Commun 235: 567-570.[CrossRef][Medline]

Champion HC, Zadina JE, Kastin AJ, and Kadowitz PJ (1997b) The endogenous µ-opioid agonists, endomorphins 1 and 2, have vasodilator activity in the hind-quarters vascular bed of the rat. Life Sci 61: PL409-PL415.[CrossRef]

Champion HC, Zadina JE, Kastin AJ, and Kadowitz PJ (1998c) Endomorphin 1 and 2 have vasodepressor activity in the anesthetized mouse. Peptides 19: 925-929.[CrossRef][Medline]

Chapman V, Diaz A, and Dickenson AH (1997) Distinct inhibitory effects of spinal endomorphin-1 and endomorphin-2 on evoked dorsal horn neuronal responses in the rat. Br J Pharmacol 122: 1537-1539.[CrossRef][Medline]

Chartrel N, Dujardin C, Anouar Y, Leprince J, Decker A, Clerens S, Do-Rego JC, Vandesande F, Llorens-Cortes C, Costentin J, et al. (2003) Identification of 26RFa, a hypothalamic neuropeptide of the RFamide peptide family with orexigenic activity. Proc Natl Acad Sci USA 100: 15247-15252.[Abstract/Free Full Text]

Chavkin C, James IF, and Goldstein A (1982) Dynorphin is a specific endogenous ligand of the opioid receptor. Science (Wash DC) 215: 413-415.[Abstract/Free Full Text]

Chen JC, Liang K-W, and Huang EY-K (2001) Differential effects of endomorphin-1 and -2 on amphetamine sensitization: neurochemical and behavioural aspects. Synapse 39: 239-248.[CrossRef][Medline]

Chen JC, Tao P-L, Li J-Y, Wong C-H, and Huang EY-K (2003) Endomorphin-1 and -2 induce naloxone-precipitated withdrawal syndromes in rats. Peptides 24: 477-481.[CrossRef][Medline]

Chesselet MF, Cheramy A, Reisine TD, and Glowinski J (1981) Morphine and µ-opiate agonists locally stimulate in vivo dopamine release in cat caudate nucleus. Nature (Lond) 291: 320-322.[CrossRef][Medline]

Chesselet MF and Delfs JM (1996) Basal ganglia and movement disorders: an update. Trends Neurosci 19: 417-422.[Medline]

Churchill L and Kalivas PW (1992) Dopamine depletion produces augmented behavioral responses to a µ-, but not a -opioid, agonist in the nucleus accumbens: lack of a role for receptor upregulation. Synapse 11: 47-57.[CrossRef][Medline]

Churchill L, Klitenick MA, and Kalivas PW (1998) Dopamine depletion reorganizes projections from the nucleus accumbens and ventral pallidum that mediate opioid-induced motor activity. J Neurosci 18: 8074-8085.[Abstract/Free Full Text]

Clark JT, Kalra PS, Crowley WR, and Kalra SP (1984) Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115: 427-429.[Abstract/Free Full Text]

Clarke G and Patrick G (1983) Differential inhibitory action by morphine on the release of oxytocin and vasopressin from the isolated neural lobe. Neurosci Lett 39: 175-180.[CrossRef][Medline]

Clarke G, Wood P, Merrick L, and Lincoln DW (1979) Opiate inhibition of peptide release from the neurohumoral terminals of hypothalamic neurones. Nature (Lond) 282: 746-748.[CrossRef][Medline]

Clouet DH and Ratner M (1970) Catecholamine biosynthesis in brains of rats treated with morphine. Science (Wash DC) 168: 854-856.[Abstract/Free Full Text]

Comer SD, Collins ED, MacArthur RB, and Fischman MW (1999) Comparison of intravenous and intranasal heroin self-administration by morphine-maintained humans. Psychopharmacol (Berl) 143: 327-338.[CrossRef][Medline]

Cosentino M, Marino F, Bombelli R, Ferrari M, Rasini E, Giaroni C, Lecchini S, and Frigo G (1997) Modulation of neurotransmitter release by opioid µ- and -receptors from adrenergic terminals in the myenteric plexus of the guinea-pig colon: effect of ₂-autoreceptor blockade. Neurosci Lett 222: 75-78.[CrossRef][Medline]

Costall B, Jones BJ, Kelly ME, Naylor RJ, and Tomkins DM (1989) Exploration of mice in a black and white test box: validation as a model of anxiety. Pharmacol Biochem Behav 32: 777-785.[CrossRef][Medline]

Coventry TL, Jessop DS, Finn DP, Crabb MD, Kinoshita H, and Harbuz MS (2001) Endomorphins and activation of the hypothalamo-pituitary-adrenal axis. J Endocrinol 169: 185-193.[Abstract]

Craft RM, Henley SR, Haaseth RC, Hruby VJ, and Porreca F (1995) Opioid antinociception in a rat model of visceral pain: systemic versus local drug administration. J Pharmacol Exp Ther 275: 1535-1542.[Abstract/Free Full Text]

Cryan JF, Mombereau C, and Vassout A (2005) The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 29: 571-625.[CrossRef][Medline]

Cunningham ST and Kelley AE (1992) Opiate infusion into nucleus accumbens: contrasting effects on motor activity and responding for conditioned reward. Brain Res 588: 104-114.[CrossRef][Medline]

Czapla MA, Champion HC, Zadina JE, Kastin AJ, Hackler L, Ge LJ, and Kadowitz PJ (1998) Endomorphin 1 and 2, endogenous µ-opioid agonists, decrease systemic arterial pressure in the rat. Life Sci 62: PL175-PL179.[CrossRef][Medline]

Czapla MA, Gozal D, Alea OA, Beckerman RC, and Zadina JE (2000) Differential cardiorespiratory effects of endomorphin 1, endomorphin 2, DAMGO, and morphine. Am J Respir Crit Care Med 162(3 Pt 1): 994-999.[Abstract/Free Full Text]

Czapla MA and Zadina JE (2005) Reduced suppression of CO₂-induced ventilatory stimulation endomorphins relative to morphine. Brain Res 1059: 159-166.[CrossRef][Medline]

Dampney RA (1994) Functional organization of central pathways regulating the cardiovascular system. Physiol Rev 74: 323-364.[Free Full Text]

Darko DF, Risch SC, Gillin JC, and Golshan S (1992) Association of β-endorphin with specific clinical symptoms of depression. Am J Psychiatry 149: 1162-1167.[Abstract/Free Full Text]

Das D, Rogers J, and Michael-Titus AT (1994) Comparative study of the effects of µ, and opioid agonists on ³H-dopamine uptake in rat striatum and nucleus accumbens, Neuropharmacology 33: 221-226.[CrossRef][Medline]

de la Baume S, Patey G, Marcais H, Protais P, Costentin J, and Schwartz C (1979) Changes in dopamine receptors in mouse striatum following morphine treatments. Life Sci 24: 2333-2342.[CrossRef][Medline]

De Vries TJ, Schoffelmeer ANM, Delay-Goyet P, Roques BP, and Mulder AH (1989) Selective effects of [D-Ser²(O-t-butyl), Leu⁵]enkephalyl-Thr⁶, and [D-Ser²(O-t-butyl), Leu⁵]enkephalyl-Thr⁶(O-t-butyl) two new enkephalin analogues, on neurotransmitter release and adenylate cyclase in rat brain slices. Eur J Pharmacol 170: 137-143.[CrossRef][Medline]

Defer N, Best-Belpomme M, and Hanoune J (2000) Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. Am J Physiol 279: F400-F416.

Delfs JM, Kong H, Mestek A, Chen Y, Yu L, Reisine T, and Chesselet M-F (1994) Expression of mu opioid receptor mRNA in rat brain: an in situ hybridization study at the single cell level. J Comp Neurol 345: 46-68.[CrossRef][Medline]

Dershwitz M, Walsh JL, Morishige RJ, Connors PM, Rubsamen RM, Shafer SL, and Rosow CE (2000) Pharmacokinetics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers. Anesthesiology 93: 619-628.[CrossRef][Medline]

Devine DP, Leone P, and Wise RA (1993) Mesolimbic dopamine neurotransmission is increased by administration of µ-opioid receptor antagonists. Eur J Pharmacol 243: 55-64.[CrossRef][Medline]

Devine DP and Wise RA (1994) Self-administration of morphine, DAMGO, and DPDPE into the ventral tegmental area of rats. J Neurosci 14: 1978-1984.[Abstract]

Di Chiara G and Imperato A (1988a) Opposite effects of mu and kappa opioid agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. J Pharmacol Exp Ther 244: 1067-1080.[Abstract/Free Full Text]

Di Chiara G and Imperato A (1988b) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85: 5274-5278.[Abstract/Free Full Text]

Doi N, Brown CH, Cohen HD, Leng G, and Russell JA (2001) Effects of the endogenous opioid peptide, endomorphin 1, on supraoptic nucleus oxytocin and vasopressin neurones in vivo and in vitro. Br J Pharmacol 132: 1136-1144.[CrossRef][Medline]

Domino EF (1979) Opiate interactions with cholinergic neurons, in Neurochemical Mechanisms of Opiates and Endorphins (Loh HH and Ross DH eds) pp 339-355, Raven, New York.

Dourmap N, Clero E, and Costentin J (1997) Involvement of cholinergic neurons in the release of dopamine elicited by stimulation of µ-opioid receptors in striatum. Brain Res 749: 295-300.[CrossRef][Medline]

Dourmap N, Michael-Titus A, and Costentin J (1992) Differential effect of intrastriatal kainic acid on the modulation of dopamine release by mu- and delta-opioid peptides: a microdialysis study. J Neurochem 58: 709-713.[CrossRef][Medline]

Driessen B and Reimann W (1992) Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. Br J Pharmacol 105: 147-151.[Medline]

D'Sa C and Duman RS (2002) Antidepressants and neuroplasticity. Bipolar Disord 4: 183-194.[CrossRef][Medline]

Dua AK, Pinsky C, and LaBella FS (1985) Peptidases that terminate the action of enkephalins: consideration of physiological importance for amino-, carboxy-, endo-, and pseudoenkephalinase. Life Sci 37: 985-992.[CrossRef][Medline]

Dun NJ, Dun SL, Wu SY, and Williams CA (2000) Endomorphins: localization, release and action on rat dorsal horn neurons. J Biomed Sci 7: 213-220.[CrossRef][Medline]

Durstewitz D, Kroner S, and Guntukun O (1999) The dopaminergic innervation of the avian telencephalon. Prog Neurobiol 59: 161-195.[CrossRef][Medline]

Duterte-Boucher D, Leclere JF, Panissaud C, and Costentin J (1988) Acute effects of direct dopamine agonists in the mouse behavioral despair test. Eur J Pharmacol 154: 185-190.[CrossRef][Medline]

Ebner K, Wotjak C, Landgraf R, and Engelmann M (2002) Forced swimming triggers vasopressin release within the amygdala to modulate stress-coping strategies in rats. Eur J Neurosci 15: 384-388.[CrossRef][Medline]

Egan MF, Ferguson JN, and Hyde TM (1995) Effects of chronic naloxone administration on vacuous chewing movements and catalepsy in rats treated with long-term haloperidol decanoate. Brain Res Bull 38: 355-363.[CrossRef][Medline]

Eghbali M, Santoro C, Paredes W, Gardner EL, and Zukin RS (1987) Visualization of multiple opioid-receptor types in rat striatum after specific mesencephalic lesions. Proc Natl Acad Sci USA 84: 6582-6586.[Abstract/Free Full Text]

Egleton RD, Abbruscato TJ, Thomas SA, and Davis TP (1998) Transport of opioid peptides into the central nervous system. J Pharm Sci 87: 1433-1439.[CrossRef][Medline]

El-Kadi AOS and Sharif SI (1998) The role of dopamine in the expression of morphine withdrawal. Gen Pharmacol 30: 499-505.[CrossRef][Medline]

Emrich HM (1982) A possible role of opioid substances in depression. Adv Biochem Psychopharmacol 32: 77-84.[Medline]

Emrich HM, Hollt V, Kissling W, Fischler M, Laspe H, Heinemann H, von Zerssen D, and Herz A (1979) β-Endorphin-like immunoreactivity in cerebrospinal fluid and plasma of patients with schizophrenia and other neuropsychiatric disorders. Pharmakopsychiatr Neuropsychopharmakol 12: 269-276.[Medline]

Erchegyi J, Kastin AJ, and Zadina JE (1992) Isolation of a novel tetrapeptide with opiate and antiopiate activity from human cortex: Tyr-Pro-Trp-Gly-NH₂ (Tyr-W-MIF-1). Peptides 13: 623-631.[CrossRef][Medline]

Eschalier A, Fialip J, Varoquaux O, and Makambila MC (1987) Study of the clomipramine-morphine interaction in the forced swimming test in mice. Psychopharmacology (Berl) 93: 515-519.[CrossRef][Medline]

Fallon JH and Leslie FM (1986) Distribution of dynorphin and enkephalin peptides in the rat brain. J Comp Neurol 249: 293-336.[CrossRef][Medline]

Fanselow MS, Calcagnetti DJ, and Helmstetter FJ (1988) Peripheral versus intracerebroventricular administration of quaternary naltrexone and the enhancement of Pavlovian conditioning. Brain Res 444: 147-152.[CrossRef][Medline]

Ferry B and McGaugh JL (2000) Role of amygdala norepinephrine in mediating stress hormone regulation of memory storage. Acta Pharmacol Sin 21: 481-493.[Medline]

Fichna J, do-Rego J-C, Kosson P, Schiller PW, Costentin J, and Janecka A (2006a) Characterization of [³⁵S]GTPS binding stimulated by endomorphin-2 and morphiceptin analogues in rat thalamus. Biochem Biophys Res Commun 345: 162-168.[CrossRef][Medline]

Fichna J, Gach K, Piestrzeniewicz M, Burgeon E, Poels J, Vanden Broeck J, and Janecka A (2006b) Functional characterization of opioid receptor ligands by aequorin luminescence-based calcium assay. J Pharmacol Exp Ther 317: 1150-1154.[Abstract/Free Full Text]

Fichna J, Janecka A, Piestrzeniewicz M, Costentin J, and do Rego J-C (2007) Antidepressant-like effect of endomorphin-1 and endomorphin-2 in mice. Neuropsychopharmacology, in press.

Fickel J, Bagnol D, Watson SJ, and Akil H (1997) Opioid receptor expression in the rat gastrointestinal tract: a quantitative study with comparison to the brain. Brain Res Mol Brain Res 46: 1-8.[Medline]

Fields HL and Basbaum AI (1978) Brain control of spinal pain transmission neurons. Annu Rev Physiol 40: 217-248.[CrossRef][Medline]

Fields HL and Basbaum AI (1994) Central nervous system mechanisms of pain modulation, in Textbook of Pain (Wall PD and Melzack R eds) pp 243-257, Churchill Livingstone, New York.

File SE and Rodgers RJ (1979) Partial anxiolytic action of morphine sulphate following microinjection into the central nucleus of the amygdala in rats. Pharmacol Biochem Behav 11: 313-318.[CrossRef][Medline]

Filliol D, Ghozland S, Chluba J, Martin M, Matthes HW, Simonin F, Befort K, Gaveriaux-Ruff C, Dierich A, LeMeur M, et al. (2000) Mice deficient for - and µ-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet 25: 195-200.[CrossRef][Medline]

Finley JC, Lindstrom P, and Petrusz P (1981) Immunocytochemical localization of β-endorphin-containing neurons in the rat brain. Neuroendocrinology 33: 28-42.[Medline]

Fischer A and Undem BJ (1999) Naloxone blocks endomorphin-1 but not endomorphin-2 induced inhibition of tachykinergic contractions of guinea-pig isolated bronchus. Br J Pharmacol 127: 605-608.[CrossRef][Medline]

Forsberg G, Bednar I, Eneroth P, and Sodersten P (1987) Naloxone reverses post-ejaculatory inhibition of sexual behaviour in female rats. J Endocrinol 113: 429-434.[Abstract/Free Full Text]

Frederickson RCA, Smithwick EL, Shuman R, and Bemis KG (1981) Metkephamid, a systemically active analog of methionine enkephalin with potent opioid -receptor activity. Science (Wash DC) 211: 603-605.[Abstract/Free Full Text]

Freeman FM and Young IG (2000) Identification of the opioid receptors involved in passive-avoidance learning in the day-old chick during the second wave of neuronal activity. Brain Res 864: 230-239.[CrossRef][Medline]

Fuentealba JA, Forray MI, and Gysling K (2000) Chronic morphine treatment and withdrawal increase extracellular levels of norepinephrine in the rat bed nucleus of the stria terminalis. J Neurochem 75: 741-748.[CrossRef][Medline]

Fuertes G, Milanes MV, Rodriguez-Gago M, Marin MT, and Laorden ML (2000) Changes in hypothalamic paraventricular nucleus catecholaminergic activity after acute and chronic morphine administration. Eur J Pharmacol 388: 49-56.[CrossRef][Medline]

Fujita T and Kumamoto E (2006) Inhibition by endomorphin-1 and endomorphin-2 of excitatory transmission in adult rat substantia gelatinosa neurons. Neuroscience 139: 1095-1105.[CrossRef][Medline]

Fürst S (1999) Transmitters involved in antinociception in the spinal cord. Brain Res Bull 48: 129-141.[CrossRef][Medline]

Gabilondo AM, Meana JJ, and Garcia-Sevilla JA (1995) Increased density of µ-opioid receptors in the postmortem brain of suicide victims. Brain Res 682: 245-250.[CrossRef][Medline]

Gaiardi M, Bartoletti M, Bacchi A, and Gubellini C (1991) Role of repeated exposure to morphine in determining its affective properties: place and taste conditioning studies in rats. Psychopharmacology (Berl) 103: 183-186.[CrossRef][Medline]

Garzon J, Rodriguez-Munoz M, Lopez-Fando A, Garcia-Espana A, and Sanchez-Blazquez PR (2004) GSZ1 and GAIP regulate µ- but not -opioid receptors in mouse CNS: role in tachyphylaxis and acute tolerance. Neuropsychopharmacology 29: 1091-1104.[CrossRef][Medline]

Gauchy C, Agid Y, Glowinski J, and Cheramy A (1973) Acute effects of morphine on dopamine synthesis and release and tyrosine metabolism in the rat striatum. Eur J Pharmacol 22: 311-319.[CrossRef][Medline]

Gentilucci L and Tolomelli A (2004) Recent advances in the investigation of the bioactive conformation of peptides active at the micro-opioid receptor: conformational analysis of endomorphins. Curr Top Med Chem 4: 105-121.[CrossRef][Medline]

Gerak LR, Brandt MR, and France CP (1998) Studies on benzodiazepines and opioids administered alone and in combination in rhesus monkeys: ventilation and drug discrimination. Psychopharmacology (Berl) 137: 164-174.[CrossRef][Medline]

Gervasoni D, Peyron C, Rampon C, Barbagli B, Chouvet G, Urbain N, Fort P, and Luppi PH (2000) Role and origin of the GABAergic innervation of dorsal raphe serotonergic neurons. J Neurosci 20: 4217-4225.[Abstract/Free Full Text]

Gholami A, Haeri-Rohani A, Sahraie H, and Zarrindast MR (2002) Nitric oxide mediation of morphine-induced place preference in the nucleus accumbens of rat. Eur J Pharmacol 449: 269-277.[CrossRef][Medline]

Gilbert CL, Boulton MI, Goode JA, and McGrath TJ (2000) The timing of parturition in the pig is altered by intravenous naloxone. Theriogenology 53: 905-923.[CrossRef][Medline]

Giraudo SQ, Billington CJ, and Levine AS (1998a) Effects of opioid antagonist naltrexone on feeding induced by DAMGO in the central nucleus of the amygdala and in the paraventricular nucleus in the rat. Brain Res 782: 18-23.[CrossRef][Medline]

Giraudo SQ, Kotz CM, Billington CJ, and Levine AS (1998b) Association between the amygdala and nucleus of the solitary tract in µ-opioid induced feeding in the rat. Brain Res 802: 184-188.[CrossRef][Medline]

Glass MJ, Billington CJ, and Levine AS (1999) Opioids and food intake: distributed functional neuronal pathways? Neuropeptides 33: 360-368.[CrossRef][Medline]

Goldberg IE, Rossi GC, Letchworth SR, Mathis JP, Ryan-Moro J, Leventhal L, Su W, Emmel D, Bolan EA, and Pasternak GW (1998) Pharmacological characterization of endomorphin-1 and endomorphin-2 in mouse brain. J Pharmacol Exp Ther 286: 1007-1013.[Abstract/Free Full Text]

Goldstein A, Tachibana S, Lowney LI, and Hold L (1979) Dynorphin A(1-13), an extraordinary potent opioid peptide. Proc Natl Acad Sci USA 76: 6666-6670.[Abstract/Free Full Text]

Gosnell BA, Levine AS, and Morley JE (1986) The stimulation of food intake by selective agonists of mu, kappa and delta opioid receptors. Life Sci 38: 1081-1088.[CrossRef][Medline]

Grahn RE, Maswood S, McQueen MB, Watkins LR, and Maier SF (1999) Opioid-dependent effects of inescapable shock on escape behavior and conditioned fear responding are mediated by the dorsal raphe nucleus. Behav Brain Res 99: 153-167.[CrossRef][Medline]

Gramsch C, Hollt V, Pasi A, Mehraein P, and Herz A (1982) Immunoreactive dynorphin in human brain and pituitary. Brain Res 233: 65-74.[CrossRef][Medline]

Granados-Soto V, Rufino MO, Gomes Lopes LD, and Ferreira SH (1997) Evidence for the involvement of the nitric oxide-cGMP pathway in the antinociception of morphine in the formalin test. Eur J Pharmacol 340: 177-180.[CrossRef][Medline]

Grass S, Xu IS, Wiesenfeld-Hallin Z, and Xu X-J (2002) Comparison of the effect of intrathecal endomorphin-1 and endomorphin-2 on spinal cord excitability in rats. Neurosci Lett 324: 197-200.[CrossRef][Medline]

Greenwald MK, Johanson C-E, and Schuster CR (1999) Opioid reinforcement in heroin-dependent volunteers during outpatient buprenorphine maintenance. Drug Alcohol Depend 56: 191-203.[CrossRef][Medline]

Grevert P and Goldstein A (1978) Endorphins: naloxone fails to alter experimental pain or mood in humans. Science (Wash DC) 199: 1093-1095.[Abstract/Free Full Text]

Grider JR and Makhlouf GM (1987) Role of opioid neurons in the regulation of intestinal peristalsis. Am J Physiol 253: G226-G231.[Medline]

Griebel G (1995) 5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders: more than 30 years of research. Pharmacol Rev Ther 65: 319-395.[CrossRef]

Griebel G (1999) Is there a future for neuropeptide receptor ligands in the treatment of anxiety disorders? Pharmacol Rev Ther 82: 1-61.[CrossRef]

Griebel G, Simiand J, Gal CS, Wagnon J, Pascal M, Scatton B, Maffrand J, and Soubrie P (2002) Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders. Proc Natl Acad Sci USA 99: 6370-6375.[Abstract/Free Full Text]

Gross-Isseroff R, Dillon KA, Israeli M, and Biegon A (1990) Regionally selective increases in µ-opioid receptor density in the brains of suicide victims. Brain Res 530: 312-316.[CrossRef][Medline]

Guilbaud G, Bernard JF, and Besson JM (1994) Brain areas involved in nociception and pain, in Textbook of Pain (Wall PD and Melzack R eds) pp 113-128, Churchill Livingstone, New York.

Guyenet PG, Stornetta RL, Schreihofer AM, Pelaez NM, Hayar A, and Aicher S (2002) Opioid signalling in the rat rostral ventrolateral medulla. Clin Exp Pharmacol Physiol 29: 238-242.[CrossRef][Medline]

Gwirtz KH, Young JV, Byers RS, Alley C, Levin K, Walker SG, and Stoelting RK (1999) The safety and efficacy of intrathecal opioid analgesia for acute postoperative pain: seven years' experience with 5969 surgical patients at Indiana University hospital. Anesth Analg 88: 599-604.[Abstract/Free Full Text]

Hackler L, Zadina JE, Ge L-J, and Kastin AJ (1997) Isolation of relatively large amounts of endomorphin-1 and endomorphin-2 from human brain cortex. Peptides 18: 1635-1639.[CrossRef][Medline]

Hagan RM and Hughes IE (1984) Opioid receptor sub-types involved in the control of transmitter release in cortex of the brain of the rat. Neuropharmacology 23: 491-495.[CrossRef][Medline]

Haigler HJ (1978) Morphine: effects on serotonergic neurons and neurons in areas with a serotonergic input. Eur J Pharmacol 51: 361-376.[CrossRef][Medline]

Haji A, Takeda R, and Okazaki M (2000) Neuropharmacology of control of respiratory rhythm and pattern in mature mammals. Pharmacol Ther 86: 277-304.[CrossRef][Medline]

Haney M, Maccari S, Le Moal M, Simon H, and Piazza PV (1995) Social stress increases the acquisition of cocaine self-administration in male and female rats. Brain Res 698: 46-52.[CrossRef][Medline]

Hao S, Takahata O, and Iwasaki H (2000) Intrathecal endomorphin-1 produces antinociceptive activities modulated by ₂-adrenoceptors in the rat tail flick, tail pressure and formalin tests. Life Sci 66: PL195-PL204.[Medline]

Harbeck HT and Mentlein R (1991) Aminopeptidase P from rat brain: purification and action on bioactive peptides. Eur J Biochem 198: 451-458.[Medline]

Harbuz MS and Lightman SL (1989) Responses of hypothalamic and pituitary mRNA to physical and psychological stress in the rat. J Endocrinol 122: 705-711.[Abstract/Free Full Text]

Harrison LM, Kastin AJ, and Zadina JE (1998) Differential effects of endomorphin-1, endomorphin-2, and Tyr-W-MIF-1 on activation of G-proteins in SH-SY5Y human neuroblastoma membranes. Peptides 19: 749-753.[CrossRef][Medline]

Hartman RD, Rosella-Dapman LM, and Summy-Long JY (1987) Endogenous opioid peptides inhibit oxytocin release in the lactating rat after dehydration and urethane. Endocrinology 121: 536-543.[Abstract/Free Full Text]

Hashimoto K, Shimizu E, and Iyo M (2004) Critical role of brain-derived factor in mood disorders. Brain Res Brain Res Rev 45: 104-114.[CrossRef][Medline]

Hatton GI (1990) Emerging concepts of structure-function dynamics in adult brain: the hypothalamo-neurohypophysial system. Prog Neurobiol 34: 437-504.[CrossRef][Medline]

Hau VS, Huber JD, Campos CR, Lipkowski AW, Misicka A, and Davis TP (2002) Effect of guanidino modification and proline substitution on the in vitro stability and blood-brain barrier permeability of endomorphin-2. J Pharm Sci 91: 2140-2149.[CrossRef][Medline]

Havemann U, Winkler M, and Kuschinsky K (1983) The effects of D-Ala², D-Leu⁵-enkephalin injections into the nucleus accumbens on the motility of rats. Life Sci 33: 627-630.[CrossRef][Medline]

Hayar A and Guyenet PG (1998) Pre- and postsynaptic inhibitory actions of methionine-enkephalin on identified bulbospinal neurons of the rat RVL. J Neurophysiol 80: 2003-2014.[Abstract/Free Full Text]

Heinricher MM, Haws CM, and Fields HL (1991) Evidence for GABA-mediated control of putative nociceptive modulating neurons in the rostra1 ventromedial medulla: iontophoresis of bicuculline eliminates the off-cell pause. Somatosens Motor Res 8: 215-225.[Medline]

Heinrichs SC, Pich EM, Miczek KA, Britton KT, and Koob GF (1992) Corticotropin-releasing factor antagonist reduces emotionality in socially defeated rats via direct neurotropic action. Brain Res 581: 190-197.[CrossRef][Medline]

Heishman SJ, Schuh KJ, Schuster CR, Henningfield JE, and Goldberg SR (2000) Reinforcing and subjective effects of morphine in human opioid abusers: effect of dose and alternative reinforcer. Psychopharmacology (Berl) 148: 272-280.[CrossRef][Medline]

Helmstetter FJ and Bellgowan PS (1993) Lesions of the amygdala block conditional hypoalgesia on the tail flick test. Brain Res 612: 253-257.[CrossRef][Medline]

Henderson G, Hugues J, and Kosterlitz HW (1979) Modification of catecholamine release by narcotic analgesics and opioid peptides, in The Release of Catecholamines from Adrenergic Neurones (Paton DM ed) pp 217-228, Pergamon, Oxford.

Henschen A, Lottspeich F, Brantl V, and Teschemacher H (1979) Novel opioid peptides derived from casein (β-casomorphins). II. Structure of active components from bovine casein peptone. Hoppe-Seyler's Z Physiol Chem 360: 1217-1224.[Medline]

Herschel M, Khoshnood B, and Lass NA (2000) Role of naloxone in newborn resuscitation. Pediatrics 106: 831-835.[Abstract/Free Full Text]

Heyne A, May T, Goll P, and Woffgramm J (2000) Persisting consequences of drug intake: towards a memory of addiction. J Neural Transm 107: 613-638.[CrossRef][Medline]

Higashida H, Hoshi N, Knijnik R, Zadina JE, and Kastin AJ (1998) Endomorphins inhibit high-threshold Ca²⁺ channel currents in rodent NG 108–15 cells overexpressing µ-opioid receptors. J Physiol (Lond) 507: 71-75.[Abstract/Free Full Text]

Higgs S and Cooper SJ (1998) Evidence for early opioid modulation of licking responses to sucrose and intralipid: a microstructural analysis in the rat. Psychopharmacology (Berl) 139: 342-355.[CrossRef][Medline]

Hill JL and Zacny JP (2000) Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers. Psychopharmacology (Berl) 152: 31-39.[CrossRef][Medline]

Hokfelt T, Ljungdahl A, Terenius L, Elde R, and Nilsson G (1977) Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia: enkephalin and substance P. Proc Natl Acad Sci USA 74: 3081-3085.[Abstract/Free Full Text]

Holaday JW (1983) Cardiovascular effects of endogenous opiate systems. Annu Rev Pharmacol Toxicol 23: 541-594.[CrossRef][Medline]

Hooks MS, Jones GH, Hemby SE, and Justice JB Jr (1993) Environmental and pharmacological sensitization: effects of repeated administration of systemic or intra-nucleus accumbens cocaine. Psychopharmacology (Berl) 111: 109-116.[CrossRef][Medline]

Hooks MS and Kalivas PW (1994) Involvement of dopamine and excitatory amino acid transmission in novelty-induced motor activity. J Pharmacol Exp Ther 269: 976-988.[Abstract/Free Full Text]

Horvath A and Kastin AJ (1989) Isolation of tyrosine-melanocyte-stimulating hormone release-inhibiting factor 1 from bovine brain tissue. J Biol Chem 264: 2175-2179.[Abstract/Free Full Text]

Horvath G (2000) Endomorphin-1 and endomorphin-2: pharmacology of the selective endogenous µ-opioid receptor agonists. Pharmacol Ther 88: 437-463.[CrossRef][Medline]

Horvath G, Szikszay M, Tomboly C, and Benedek G (1999) Antinociceptive effects of intrathecal endomorphin-1 and -2 in rats. Life Sci 65: 2635-2641.[CrossRef][Medline]

Howlett TA and Rees LH (1986) Endogenous opioid peptides and hypothalamopituitary function. Annu Rev Physiol 48: 527-536.[CrossRef][Medline]

Huang C, Wang Y, Chang J-K, and Han J-S (2000) Endomorphin and µ-opioid receptors in mouse brain mediate the analgesic effect induced by 2 Hz but not 100 Hz electroacupuncture stimulation. Neurosci Lett 294: 159-162.[CrossRef][Medline]

Huang EY-K, Chen C-M, and Tao P-L (2004) Supraspinal anti-allodynic and rewarding effects of endomorphins in rats. Peptides 25: 577-583.[CrossRef][Medline]

Huang EJ and Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24: 677-736.[CrossRef][Medline]

Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan GA, and Morris HR (1975) Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature (Lond) 258: 577-580.[CrossRef][Medline]

Hui R, Chen T, and Li Y-Q (2006) The reciprocal connections of endomorphin 1- and endomorphin 2-containing neurons between the hypothalamus and nucleus tractus solitarii in the rat. Neuroscience 138: 171-181.[CrossRef][Medline]

Hung K-C, Wu H-E, Mizoguchi H, Leitermann R, and Tseng LF (2003) Intrathecal treatment with 6-hydroxydopamine or 5,7-dihydroxytryptamine blocks the antinociception induced by endomorphin-1 and endomorphin-2 given intracerebroventricularly in the mouse. J Pharmacol Sci 93: 299-306.[CrossRef][Medline]

Hung K-C, Wu H-E, Mizoguchi H, and Tseng LF (2002) Acute antinociceptive tolerance and unidirectional cross-tolerance to endomorphin-1 and endomorphin-2 given intraventricularly in the rat. Eur J Pharmacol 448: 169-174.[CrossRef][Medline]

Hunt WA and Lands WEM (1992) A role for behavioral sensitization in uncontrolled ethanol intake. Alcohol 9: 327-328.[CrossRef][Medline]

Ignar DM and Kuhn CM (1990) Effects of specific mu and kappa opiate tolerance and abstinence on hypothalamo-pituitary-adrenal axis secretion in the rat. J Pharmacol Exp Ther 255: 1287-1295.[Abstract/Free Full Text]

Illes P (1989) Modulation of transmitter and hormone release by multiple neuronal opioid receptors. Rev Physiol Biochem Pharmacol 112: 139-233.[Medline]

Introini IB and Baratti CM (1986) Opioid peptidergic systems may modulate the activity of β-adrenergic mechanisms during memory consolidation processes. Behav Neural Biol 46: 227-241.[CrossRef][Medline]

Introini IB, McGaugh JL, and Baratti CM (1985) Pharmacological evidence of a central effect of naltrexone, morphine, β-endorphin and a peripheral effect of met- and leu-enkephalin on retention of an inhibitory response in mice. Behav Neural Biol 44: 434-446.[CrossRef][Medline]

Inui A, Okita M, Nakajima M, Inoue T, Sakatani N, Oya M, Morioka H, Okimura Y, Chihara K, and Baba S (1991) Neuropeptide regulation of feeding in dogs. Am J Physiol 261(Pt 2): R588—R594.[Medline]

Itoh E, Fujimiya M, and Inui A (1998) Thioperamide, a histamine H3 receptor antagonist, suppresses NPY-but not dynorphin A-induced feeding in rats. Regul Pept 75-76: 373-376.[CrossRef][Medline]

Itoh J, Ukai M, and Kameyama T (1994) Dynorphin A(1-13) potently improves the impairment of spontaneous alternation performance induced by the m-selective opioid receptor agonist DAMGO in mice. J Pharmacol Exp Ther 269: 15-21.[Abstract/Free Full Text]

Iwamoto ET and Way EL (1979) Opiate actions and catecholamines, in Neurochemical Mechanisms of Opiates and Endorphins (Loh HH and Ross DH eds) pp 357-407, Raven, New York.

Izquierdo I (1979) Effect of naloxone and morphine on various forms of memory in the rat: possible role of endogenous opiate mechanisms in memory consolidation. Psychopharmacology (Berl) 66: 199-203.[CrossRef][Medline]

Izzo PN and Sykes RM (1992) -Aminobutyric acid immunoreactive structures in the nucleus tractus solitarius: a light and electron microscopic study. Brain Res 591: 69-78.[CrossRef][Medline]

Jackisch R (1991) Regulation of neurotransmitter release by opiates and opioid peptides in the central nervous system, in Presynaptic Regulation of Neurotransmitter Release: a Handbook (Feigenbaum J and Hanani M eds) pp 551-592, Freund Publishing House, Tel Aviv.

Jakab RL and Leranth C (1995) Septum, in The Rat Nervous System (Paxinos G ed) pp 405-442, Academic Press, San Diego.

Jamurtas AZ, Goldfarb AH, Chung S-C, Hegde S, and Marino C (2000) β-Endorphin infusion during exercise in rats: blood metabolic effects. Med Sci Sports Exerc 10: 1570-1575.[CrossRef]

Janecka A and Kruszynski R (2005) Conformationally restricted peptides as tools in opioid receptor studies. Curr Med Chem 12: 471-481.[Medline]

Janecka A, Fichna J, and Janecki T (2004) Opioid receptors and their ligands. Curr Top Med Chem 4: 1-17.[Medline]

Janecka A, Kruszynski R, Fichna J, Kosson P, and Janecki T (2006) Enzymatic degradation studies of endomorphin-2 and its analogs containing N-methylated amino acids. Peptides 27: 131-135.[CrossRef][Medline]

Jang CG, Lee SY, Park Y, Ma T, Loh HH, and Ho IK (2001) Differential effects of morphine, DPDPE, and U-50488 on apomorphine-induced climbing behavior in µ-opioid receptor knockout mice. Mol Brain Res 94: 197-199.[Medline]

Jang CG, Park Y, Tanaka S, Ma T, Loh HH, and Ho IK (2000) Involvement of µ-opioid receptors in potentiation of apomorphine-induced climbing behavior by morphine: studies using µ-opioid receptor gene knockout mice. Mol Brain Res 78: 204-206.[Medline]

Jessop DS, Major GN, Coventry TL, Kaye SJ, Fulford AJ, Harbuz MS, and De Bree FM (2000) Novel opioid peptides endomorphin-1 and endomorphin-2 are present in mammalian immune tissues. J Neuroimmunol 106: 53-59.[CrossRef][Medline]

Jhamandas K and Sutak M (1980) Action of enkephalin analogues and morphine on brain acetylcholine release: differential reversal by naloxone and an opiate brain pentapeptide. Br J Pharmacol 71: 201-210.[Medline]

Johansson O, Hokfelt T, Elde RP, Schultzberg M, and Terenius L (1978) Immunohistochemical distribution of enkephalin neurons. Adv Biochem Psychopharmacol 18: 51-70.[Medline]

Johnson K, Churchill L, Klitenick MA, Hooks MS, and Kalivas PW (1996) Involvement of the ventral tegmental area in locomotion elicited from the nucleus accumbens or ventral pallidum. J Pharmacol Exp Ther 277: 1122-1131.[Abstract/Free Full Text]

Johnson MW, Mitch WE, and Wilcox CS (1985) The cardiovascular actions of morphine and the endogenous opioid peptides. Prog Cardiovasc Dis 27: 435-450.[CrossRef][Medline]

Johnson SW and North RA (1992) Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 12: 483-488.[Abstract]

Jolas T and Aghajanian GK (1997) Opioids suppress spontaneous and NMDA-induced inhibitory postsynaptic currents in the dorsal raphe nucleus of the rat in vitro. Brain Res 755: 229-245.[CrossRef][Medline]

Jones SL (1991) Descending noradrenergic influences on pain. Prog Brain Res 88: 381-394.[Medline]

Joyce EM and Iversen SD (1979) The effect of morphine applied locally to mesencephalic dopamine cell bodies on spontaneous motor activity in the rat. Neurosci Lett 14: 207-212.[CrossRef][Medline]

Kakizawa K, Shimohira I, Sakurada S, Fujimura T, Murayama K, and Ueda H (1998) Parallel stimulations of in vitro and in situ [³⁵S]GTPS binding by endomorphin 1 and DAMGO in mouse brains. Peptides 19: 755-758.[CrossRef][Medline]

Kalyuzhny AE, Arvidsson U, Wu W, and Wessendorf MW (1996) µ-Opioid and -opioid receptors are expressed in brainstem antinociceptive circuits: studies using immunocytochemistry and retrograde tract-tracing. J Neurosci 16: 6490-6503.[Abstract/Free Full Text]

Kalyuzhny AE and Wessendorf MW (1997) CNS GABA neurons express the muopioid receptor: immunocytochemical studies. NeuroReport 8: 3367-3372.[Medline]

Kameyama T, Ukai M, and Shinkai N (1998) Ameliorative effects of tachykinins on scopolamine-induced impairment of spontaneous alternation performance in mice. Methods Find Exp Clin Pharmacol 20: 555-560.[CrossRef][Medline]

Kang W, Wilson SP, and Wilson MA (2000) Overexpression of proenkephalin in the amygdala potentiates the anxiolytic effects of benzodiazepines. Neuropsychopharmacology 22: 77-88.[CrossRef][Medline]

Kang YS and Park JH (2000) Brain uptake and the analgesic effect of oxytocin—its usefulness as an analgesic agent. Arch Pharm Res (NY) 23: 391-395.

Kanjhan R (1995) Opioids and pain. Clin Exp Pharmacol Physiol 22: 397-403.[Medline]

Karler R, Chaudhry IA, Calder LD, and Turkanis SA (1990) Amphetamine behavioral sensitization and the excitatory amino acids. Brain Res 537: 76-82.[CrossRef][Medline]

Kasamatsu K and Chitravanshi VC (2004) Depressor and bradycardic responses to microinjections of endomorphin-2 into the NTS are mediated via ionotropic glutamate receptors. Am J Physiol 287: R715-R728.[CrossRef]

Kastin AJ, Scollan EL, Ehrensing RH, Schally AV, and Coy DH (1978) Enkephalin and other peptides reduce passiveness. Pharmacol Biochem Behav 9: 515-519.[CrossRef][Medline]

Kato S (1998) Suppression of inspiratory fast rhythm, but not bilateral short-term synchronization, by morphine in anesthetized rabbit. Neurosci Lett 258: 89-92.[CrossRef][Medline]

Kato T, Nagatsu T, Kiura T, and Sakakibara S (1978) Studies on substrate specificity of X-prolyl dipeptidyl-aminopeptidase using new chromogenic substrates X-Y-p-nitroanilides. Experientia (Basel) 15: 319-320.

Katz RJ (1979) Opiate stimulation increases exploration in the mouse. Int J Neurosci 9: 213-215.[Medline]

Kawahara H, Yoshida M, Yokoo H, Nishi M, and Tanaka M (1993) Psychological stress increases serotonin release in the rat amygdala and prefrontal cortex assessed by in vivo microdialysis. Neurosci Lett 162: 81-84.[CrossRef][Medline]

Kaye WH (1997) Persistent alterations in behaviour and serotonin activity after recovery from anorexia and bulimia nervosa. Ann NY Acad Sci 817: 162-178.[CrossRef][Medline]

Keller M, Boissard C, Patiny L, Chung NN, Lemieux C, Mutter M, and Schiller PW (2001) Pseudoproline-containing analogues of morphiceptin and endomorphin-2: evidence for a cis Tyr-Pro amide bond in the bioactive conformation. J Med Chem 44: 3896-3903.[CrossRef][Medline]

Kest B, McLemore GL, Sadowski B, Mogil JS, Belknap JK, and Inturrisi CE (1998) Acute morphine dependence in mice selectively-bred for high and low analgesia. Neurosci Lett 256: 120-122.[CrossRef][Medline]

Khachaturian H, Lewis ME, Schaefer MK-H, and Watson SJ (1985) Anatomy of the CNS opioid systems. Trends Neurosci 7: 111-119.[CrossRef]

Kiefel JM, Cooper ML, and Bodnar RJ (1992a) Inhibition of mesencephalic morphine analgesia by methysergide in the medial ventral medulla of rats. Physiol Behav 51: 201-205.[CrossRef][Medline]

Kiefel JM, Cooper ML, and Bodnar RJ (1992b) Serotonin receptor subtype antagonists in the medial ventral medulla inhibit mesencephalic opiate analgesia. Brain Res 597: 331-338.[CrossRef][Medline]

Kimmel HL, Justice JB Jr, and Holtzman SG (1998) Dissociation of morphine-induced potentiation of turning and striatal dopamine release by amphetamine in the nigrally lesioned rat. Eur J Pharmacol 346: 203-208.[CrossRef][Medline]

Kishioka S, Ko MC, and Woods JH (2000a) Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys. Eur J Pharmacol 397: 85-92.[CrossRef][Medline]

Kishioka S, Paronis CA, and Woods JH (2000b) Acute dependence on, but not tolerance to, heroin and morphine as measured by respiratory effects in rhesus monkeys. Eur J Pharmacol 398: 121-130.[CrossRef][Medline]

Kline NS, Li CH, Lehman HL, Lajta A, Laski E, and Cooper T (1977) β-Endorphin-induced changes in schizophrenics and depressed patients. Arch Gen Psychiatry 34: 1111-1113.[Abstract/Free Full Text]

Koks S, Soosaar A, Voikar V, Bourin M, and Vasar E (1999) BOC-CCK-4, CCK_B receptor agonist, antagonizes anxiolytic-like action of morphine in elevated plusmaze. Neuropeptides 33: 63-69.[CrossRef][Medline]

Kolesnikov Y and Pasternak GW (1999) Topical opioids in mice: analgesia and reversal tolerance by a topical N-methyl-D-aspartate antagonist. J Pharmacol Exp Ther 290: 247-252.[Abstract/Free Full Text]

Kraepelin E (1905) Die Psychiatrische Klinic. Barth, Leipzig.

Kreek MJ, Borg L, Zhou Y, and Schluger J (2002) Relationships between endocrine functions and substance abuse syndromes: heroin and related short-acting opiates in addiction contrasted with methadone and other long-acting opioid agonists used in pharmacotherapy of addiction, in Hormones, Brain and Behavior (Pfaff D ed) pp 781-830, Academic Press, San Diego.

Kreek MJ and Koob GF (1998) Drug dependence: stress and dysregulation of brain reward pathways. Drug Alcohol Depend 51: 23-47.[CrossRef][Medline]

Kreil G, Barra D, Simmaco M, Erspamer V, Falconieri-Erspamer G, Negri L, Severini C, Corsi R, and Melchiorri P (1989) Deltorphin, a novel amphibian skin peptide with high selectivity and affinity for delta opioid receptors. Eur J Pharmacol 162: 123-128.[CrossRef][Medline]

Krenn H, Jellinek H, Haumer H, Oczenski W, and Fitzgerald R (2000) Naloxone-resistant respiratory depression and neurological eye symptoms after intrathecal morphine. Anesth Analg 91: 432-433.[Abstract/Free Full Text]

Krettek JE and Price JL (1977) The cortical projections of the mediodorsal nucleus and adjacent thalamic nuclei in the rat. J Comp Neurol 171: 157-191.[CrossRef][Medline]

Kudryavtseva NN (1994) Experience of defeat decreases the behavioural reactivity to conspecifics in the partition test. Behav Proc 32: 297-304.[CrossRef]

Kudryavtseva NN, Bakshtanovskaya IV, and Koryakina LA (1991) Social model of depression in mice of C57BL/6J strain. Pharmacol Biochem Behav 38: 315-320.[CrossRef][Medline]

Kuhn CM and Windh RT (1989) Endocrine actions of opiates, in Biochemistry and Physiology of Substance Abuse (Watson RR ed) pp 247-277, CRC Press, Boca Raton, FL.

Kuzmin A, Sandin J, Terenius L, and Ogren SO (2000) Dose- and time-dependent bimodal effects of -opioid agonists on locomotor activity in mice. J Pharmacol Exp Ther 295: 1031-1042.[Abstract/Free Full Text]

Kwok EH and Dun NJ (1998) Endomorphins decrease heart rate and blood pressure possibly by activating vagal afferents in anesthetized rats. Brain Res 803: 204-207.[CrossRef][Medline]

LaBuda CJ, Sora I, Uhl GR, and Fuchs PN (2000) Stress-induced analgesia in µ-opioid receptor knockout mice reveals normal function of the µ-opioid receptor system. Brain Res 869: 1-5.[CrossRef][Medline]

Labuz D, Przewlocki R, and Przewlocka B (2002) Cross-tolerance between the different µ-opioid receptor agonists endomorphin-1, endomorphin-2 and morphine at the spinal level in the rat. Neurosci Lett 334: 127-130.[CrossRef][Medline]

Langer SZ (1981) Presynaptic regulation of the release of catecholamines. Pharmacol Rev 32: 337-361.

Laorden ML, Fuertes G, Gonzalez-Cuello A, and Milanes MV (2000) Changes in catecholaminergic pathways innervating paraventricular nucleus and pituitary-adrenal axis response during morphine dependence: implication of ₁- and ₂-adrenoceptors. J Pharmacol Exp Ther 293: 578-584.[Abstract/Free Full Text]

Latimer LG, Duffy P, and Kalivas PW (1987) Mu opioid receptor involvement in enkephalin activation of dopamine neurons in the ventral tegmental area. J Pharmacol Exp Ther 241: 328-337.[Abstract/Free Full Text]

Law P-Y, Wong YH, and Loh HH (2000) Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol 40: 389-430.[CrossRef][Medline]

Le Merrer J, Cagniard B, and Cazala P (2006) Modulation of anxiety by µ-opioid receptors of the lateral septal region in mice. Pharmacol Biochem Behav 83: 465-479.[CrossRef][Medline]

Leone P, Pocock D, and Wise RA (1991) Morphine-dopamine interaction: ventral tegmental morphine increases nucleus accumbens dopamine release. Pharmacol Biochem Behav 39: 469-472.[CrossRef][Medline]

Leventhal L, Mathis JP, Rossi GC, Pasternak GW, and Bodnar RJ (1998a) Orphan opioid receptor antisense probes block orphanin FQ-induced hyperphagia. Eur J Pharmacol 349: R1-R2.[CrossRef][Medline]

Leventhal L, Silva RM, Rossi GC, Pasternak GW, and Bodnar RJ (1998b) Morphine-6β-glucuronide-induced hyperphagia: characterization of opioid action by selective antagonists and antisense mapping in rats. J Pharmacol Exp Ther 287: 538-544.[Abstract/Free Full Text]

Lewis DA, Campbell MJ, Foote SL, Goldstein M, and Morrison JH (1987) The distribution of tyrosine hydroxylase-immunoreactive fibers in primate neocortex is widespread but regionally specific. J Neurosci 7: 279-290.[Abstract]

Li CH and Chung D (1976) Isolation and structure of an untriakontapeptide with opiate activity from camel pituitary glands. Proc Natl Acad Sci USA 73: 1145-1148.[Abstract/Free Full Text]

Li Z-H, Shan L-D, Jiang X-H, Guo S-Y, Yu G-Di, Hisamitsu T, and Yin Q-Z (2001) Analgesic effect of endomorphin-1. Acta Pharmacol Sin 22: 976-980.[Medline]

Liebsch G, Wotjak CT, Landgraf R, and Engelmann M (1996) Septal vasopressin modulates anxiety-related behavior in rats. Neurosci Lett 217: 101-104.[CrossRef][Medline]

Lindstrom LH, Widerlov E, Gunne LM, Wahlstrom A, and Terenius L (1978) Endorphins in human cerebrospinal fluid: clinical correlations to some psychotic states. Acta Psychiatr Scand 57: 153-164.[Medline]

Lioudyno MI, Verbitsky M, Glowatzki E, Holt JC, Boulter J, Zadina JE, Elgoyhen AB, and Guth PS (2002) The 9/10-containing nicotinic ACh receptor is directly modulated by opioid peptides, endomorphin-1, and dynorphin B, proposed efferent cotransmitters in the inner ear. Mol Cell Neurosci 20: 695-711.[CrossRef][Medline]

Lipp J (1991) Possible mechanisms of morphine analgesia. Clin Neuropharmacol 14: 131-147.[Medline]

Lippl F, Schusdziarra V, and Allescher HD (2001) Effect of endomorphin on somatostatin secretion in the isolated perfused rat stomach. Neuropeptides 35: 303-309.[CrossRef][Medline]

Liu ZJ, Zhuang DB, Lundeberg T, and Yu LC (2002) Involvement of 5-hydroxytryptaminel A receptors in the descending anti-nociceptive pathway from periaqueductal grey to the spinal dorsal horn in tract rats, rats with inflammation. Neuroscience 112: 399-407.[CrossRef][Medline]

Locke KW and Holtzman SG (1986) Behavioral effects of opioid peptides selective for mu or delta receptors: II. Locomotor activity in nondependent and morphine-dependent rats. J Pharmacol Exp Ther 238: 997-1003.[Abstract/Free Full Text]

Loh HH, Liu H-C, Cavalli A, Yang W, Chen Y-F, and Wei L-N (1998) µ-Opioid receptor knockout in mice: effects on ligand-induced analgesia and morphine lethality. Mol Brain Res 54: 321-326.[Medline]

Longoni R, Spina L, Mulas A, Carboni E, Garau L, Melchiorri P, and Di Chiara G (1991) (D-Ala²)Deltorphin II: Dl-dependent stereotypies and stimulation of dopamine release in the nucleus accumbens. J Neurosci 11: 1565-1576.[Abstract]

Loughlin SE, Leslie FM, and Fallon JH (1995) Endogenous opioid systems, in The Rat Nervous System (Paxinos G ed) pp 975-1001, Academic Press, San Diego.

Louvel D, Delaveux M, Felez A, Fioramonti J, Bueno L, Lazorthes Y, and Frexinos J (1996) Oxytocin increases thresholds of clonic visceral perception in patients with irritable bowel syndrome. Gut 39: 741-747.[Abstract/Free Full Text]

Lundeberg T, Uvnas-Moberg K, Agren G, and Bruzelius G (1994) Antinociceptive effects of oxytocin in rats and mice. Neurosci Lett 170: 153-157.[CrossRef][Medline]

Ma D, Sapsed-Byrne SM, Chakrabarti MK, and Whitwam JG (1998) Synergistic interaction between the effects of propofol and midazolam with fentanyl on phrenic nerve activity in rabbits. Acta Anesthesiol Scand 42: 670-677.[Medline]

Ma QP and Han JS (1992) Neurochemical and morphological evidence of an antinociceptive neural pathway from nucleus raphe dorsalis to nucleus accumbens in the rabbit. Brain Res Bull 28: 931-936.[CrossRef][Medline]

Makino M, Kitano Y, Komiyama C, Hirohashi M, Kohno M, Moriyama M, and Takasuna K (2000a) Human interferon- induces immobility in the mouse forced swimming test: involvement of the opioid system. Brain Res 852: 482-484.[CrossRef][Medline]

Makino M, Kitano Y, Komiyama C, Hirohashi M, and Takasuna K (2000b) Involvement of central opioid systems in human interferon- induced immobility in the mouse forced swimming test. Br J Pharmacol 130: 1269-1274.[CrossRef][Medline]

Makulska-Nowak HE, Gumulka SW, Lipkowski AW, and Rawa MA (2001) Effects of endomorphin-2 on arterial blood pressure and pain threshold in spontaneously hypertensive rats and modification of these effects by β-funaltrexamine and norbinaltorphimine. Life Sci 69: 581-589.[CrossRef][Medline]

Malcangio M and Lessmann V (2003) A common thread for pain and memory synapses? Brain-derived neurotrophic factor and trkB receptors. Trends Pharmacol Sci 24: 116-121.[CrossRef][Medline]

Manning BH and Mayer DJ (1995) The central nucleus of the amygdala contributes to the production of morphine antinociception in the formalin test. Pain 63: 141-152.[CrossRef][Medline]

Mansour A, Fox CA, Akil H, and Watson SJ (1995) Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci 18: 22-29.[CrossRef][Medline]

Mansour A, Fox CA, Burke S, Meng F, Thompson RC, Akil H, and Watson SJ (1994) Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study. J Comp Neurol 350: 412-438.[CrossRef][Medline]

Mansour A, Khachaturian H, Lewis ME, Akil H, and Watson SJ (1988) Anatomy of CNS opioid receptors. Trends Neurosci 11: 308-314.[CrossRef][Medline]

Mansour A, Lewis ME, Khachaturian H, Akil H, and Watson SJ (1986) Pharmacological and anatomical evidence of selective µ, and opioid receptor binding in rat brain. Brain Res 399: 69-79.[CrossRef][Medline]

Maqbool AT, Batten FC, and McWilliam PN (1991) Ultrastructural relationships between GABAergic terminals and cardiac vagal preganglionic motoneurons and vagal afferents in the cat: a combined HRP tracing and immunogold labelling study. Eur J Neurosci 3: 501-513.[CrossRef][Medline]

Marek GJ and Aghajanian GK (1998) 5-Hydroxytryptamine-induced excitatory postsynaptic currents in neocortical layer V pyramidal cells: suppression by muopiate receptor activation. Neuroscience 86: 485-497.[CrossRef][Medline]

Margolis EB, Hjelmstad GO, Bonci A, and Fields HL (2003) -Opioid agonists directly inhibit midbrain dopaminergic neurons. J Neurosci 23: 9981-9986.[Abstract/Free Full Text]

Martin WR (1983) Pharmacology of opioids. Pharmacol Rev 35: 283-323.[Abstract]

Martinez M, Calvo-Torrent A, and Pico-Alfonso MA (1998) Social defeat and subordination as models of social stress in laboratory rodents: a review. Aggress Behav 24: 241-256.[CrossRef]

Martin-Schild S, Gerall AA, Kastin AJ, and Zadina JE (1998) Endomorphin-2 is an endogenous opioid in primary sensory afferent fibers. Peptides 19: 1783-1789.[CrossRef][Medline]

Martin-Schild S, Gerall AA, Kastin AJ, and Zadina JE (1999) Differential distribution of endomorphin 1- and endomorphin-2-like immunoreactivities in the CNS of the rodent. J Comp Neurol 405: 450-471.[CrossRef][Medline]

Martin-Schild S, Zadina JE, Gerall AA, Vigh S, and Kastin AJ (1997) Localization of endomorphin-2-like immunoreactivity in the rat medulla and spinal cord. Peptides 18: 1641-1649.[CrossRef][Medline]

Matsuo R, Shimizu N, and Kusano K (1984) Lateral hypothalamic modulation of oral sensory afferent activity in nucleus tractus solitarius neurons of rats. J Neurosci 4: 1201-1207.[Abstract]

Matsuzawa S, Suzuki T, and Misawa M (2000) Involvement of µ-opioid receptor in the salsolinol-associated place preference in rats exposed to conditioned fear stress. Alcohol Clin Exp Res 24: 366-372.[Medline]

McConalogue K, Grady EF, Minnis J, Balestra B, Tonini M, Brecha NC, Bunnett NC, and Sternini C (1999) Activation and internalization of the µ-opioid receptor by the newly discovered endogenous agonists, endomorphin-1 and endomorphin-2. Neuroscience 90: 1051-1059.[CrossRef][Medline]

McCormick DA, Pape HC, and Williamson A (1991) Actions of norepinephrine in the cerebral cortex and thalamus: implications for function of the central noradrenergic system. Prog Brain Res 88: 293-305.[Medline]

McGowan MK and Hammond DL (1993a) Antinociception produced by microinjection of L-glutamate into the ventromedial medulla of the rat: mediation by spinal GABA-A receptors. Brain Res 620: 86-96.[CrossRef][Medline]

McGowan MK and Hammond DL (1993b) Intrathecal GABA-B antagonists attenuate the antinociception produced by microinjection of L-glutamate into the ventromedial medulla of the rat. Brain Res 607: 39-46.[CrossRef][Medline]

McIntosh CH, Jia X, and Kowk YN (1990) Characterization of the opioid receptor type mediating inhibition of rat gastric somatostatin secretion. Am J Physiol 259: G922-G927.[Medline]

Meehan WP, Tornatzky W, and Miczek KA (1995) Blood pressure via telemetry during social confrontations in rats: effects of clonidine. Physiol Behav 58: 81-88.[CrossRef][Medline]

Mehta A, Bot G, Reisine T, and Chesselet M-F (2001) Endomorphin-1: induction of motor behavior and lack of receptor desensitization. J Neurosci 21: 4436-4442.[Abstract/Free Full Text]

Mellon RD and Bayer BM (1998) Role of central receptor subtypes in morphine-induced alterations in peripheral lymphocyte activity. Brain Res 789: 56-67.[CrossRef][Medline]

Menard J and Treit D (1999) Effects of centrally administered anxiolytic compounds in animal models of anxiety. Neurosci Biobehav Rev 23: 591-613.[CrossRef][Medline]

Mendelson J, Jones RT, Welm S, Baggott M, Fernandez I, Melby AK, and Nath RP (1999) Buprenorphine and naloxone combinations: the effects of three dose ratios in morphine-stabilized, opiate-dependent volunteers. Psychopharmacology (Berl) 141: 37-46.[CrossRef][Medline]

Mercer ME and Holder MD (1997) Food cravings, endogenous opioid peptides, and food intake: a review. Appetite 29: 325-352.[CrossRef][Medline]

Metzger M, Jiang S, Wang J, and Braun K (1996) Organization of the dopaminergic innervation of forebrain areas relevant to learning: a combined immunohistochemical/retrograde tracing study in the domestic chick. J Comp Neurol 376: 1-27.[CrossRef][Medline]

Meunier J-C, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour J-L, Guillemot J-C, Ferrara P, Monsarrat B, et al. (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature (Lond) 377: 532-535.[CrossRef][Medline]

Miczek KA, Thompson ML, and Tornatzky W (1991) Subordinate animals: behavioral and physiological adaptations and opioid tolerance, in Neurobiology and Neuroendocrinology of Stress (Brown MR, Koob GF, and Rivier C eds) pp 323-357, Marcel Dekker, New York.

Milanes MV, Laorden ML, Chapleur-Chateau M, and Burlet A (1998) Alterations in corticotropin-releasing factor and vasopressin content in rat brain during morphine withdrawal: correlation with hypothalamic noradrenergic activity and pituitary-adrenal response. J Pharmacol Exp Ther 285: 700-706.[Abstract/Free Full Text]

Millan MJ and Duka T (1981) Anxiolytic properties of opiates and endogenous opioid peptides and their relationship to the actions of benzodiazepines. Mod Probl Pharmacopsychiatry 17: 123-141.[Medline]

Millan MJ and Herz A (1985) The endocrinology of the opioids. Int Rev Neurobiol 26: 1-83.[Medline]

Miranda HF and Pinardi G (1998) Antinociception, tolerance, and physical dependence comparison between morphine and tramadol. Pharm Biochem Behav 61: 357-360.[CrossRef][Medline]

Mizoguchi H, Narita M, Wu H-E, Narita M, Suzuki T, Nagase H, and Tseng LF (2000) Differential involvement of µ₁-opioid receptors in endomorphin and µ-endorphin-induced G-protein activation in the mouse pons/medulla. Neuroscience 100: 835-839.[CrossRef][Medline]

Morgan MM, Whitney PK, and Gold MS (1998) Immobility and flight associated with antinociception produced by activation of the ventral and lateral/dorsal regions of the rat periaqueductal gray. Brain Res 804: 159-166.[CrossRef][Medline]

Morley JE, Levine AS, Grace M, and Kniep J (1982) An investigation of the role of kappa opiate receptor agonists in the initiation of feeding. Life Sci 31: 2617-2626.[CrossRef][Medline]

Morley JE, Levine AS, Yim GK, and Lowy MT (1983) Opioid modulation of appetite. Neurosci Biobehav Rev 7: 281-305.[CrossRef][Medline]

Moss IR (2000) Respiratory responses to single and episodic hypoxia during development: mechanisms of adaptation. Resp Physiol 121: 185-197.[CrossRef][Medline]

Moss IR and Laferriere A (2000) Prenatal cocaine raises µ-opioid receptor density in piglet cardiorespiratory medulla. Neurotoxicol Teratol 22: 3-10.[CrossRef][Medline]

Motta V and Brandao ML (1993) Aversive and antiaversive effects of morphine in the dorsal periaqueductal gray of rats submitted to the elevated plus-maze test. Pharmacol Biochem Behav 44: 119-125.[CrossRef][Medline]

Motta V, Penha K, and Brandao ML (1995) Effects of microinjections of mu and kappa receptor agonists into the dorsal periaqueductal gray of rats submitted to the plus maze test. Psychopharmacology (Berl) 120: 470-474.[CrossRef][Medline]

Moufid-Bellancourt S and Velley L (1994) Effects of morphine injection into the parabrachial area on saccharin preference: modulation by lateral hypothalamic neurons. Pharmacol Biochem Behav 48: 127-133.[CrossRef][Medline]

Mousa SA, Machelska H, Schafer M, and Stein C (2002) Immunohistochemical localization of endomorphin-1 and endomorphin-2 in immune cells and spinal cord in a model of inflammatory pain. J Neuroimmunol 126: 5-15.[CrossRef][Medline]

Mulder AH, Burger DM, Wardeh G, Hogenboom F, and Frankhuyzen AL (1991a) Pharmacological profile of various -agonists at -, µ-, and -opioid receptors mediating presynaptic inhibition of neurotransmitter release in the rat brain. Br J Pharmacol 102: 518-522.[Medline]

Mulder AH and Schoffelmeer ANM (1993) Multiple opioid receptors and presynaptic modulation of neurotransmitter release in the brain, in Opioids: Handbook of Experimental Pharmacology (Herz A, Akil H, and Simon EJ eds) pp 125-144, Springer, Berlin.

Mulder AH, Wardeh G, Hogenboom F, and Frankhuyzen AL (1989) Selectivity of various opioid peptides towards delta-, kappa-, and mu-opioid receptors mediating presynaptic inhibition of neurotransmitter release in the rat brain. Neuropeptides 14: 99-104.[CrossRef][Medline]

Mulder AH, Wardeh G, Hogenboom F, Kazmierski W, Hruby VJ, and Schoffelmeer ANM (1991b) Cyclic somatostatin analogues as potent antagonists at µ-, but not - and -opioid receptors mediating inhibition of neurotransmitter release in the brain. Eur J Pharmacol 205: 1-6.[CrossRef][Medline]

Nakanishi S, Inoue A, Kita T, Chang ACY, Cohen S, and Numa S (1979) Nucleotide sequence of cloned cDNA for bovine corticotropin-β-lipotropin precursor. Nature (Lond) 257: 238-240.[CrossRef]

Narita M, Mizoguchi H, Narita M, Dun NJ, Hwang BH, Endoh T, Suzuki T, Nagase H, Suzuki T, and Tseng LF (2000) G protein activation by endomorphins in the mouse periaqueductal gray matter. J Biomed Sci 7: 221-225.[CrossRef][Medline]

Narita M, Mizoguchi H, Narita M, Sora I, Uhl GR, and Tseng LF (1999) Absence of G-protein activation by µ-opioid receptor agonists in the spinal cord of µ-opioid receptor knockout mice. Br J Pharmacol 126: 451-456.[CrossRef][Medline]

Narita M, Ozaki S, Ioka M, Mizoguchi H, Nagase H, Tseng LF, and Suzuki T (2001a) Different motivational effects induced by the endogenous µ-opioid receptor ligands endomorphin-1 and -2 in the mouse. Neuroscience 105: 213-218.[CrossRef][Medline]

Narita M, Ozaki S, Ioka M, Mizoguchi H, Nagase H, Tseng LF, and Suzuki T (2001b) Lack of the involvement of mu1-opioid receptor subtype on motivational effects induced by the endogenous µ-opioid receptor ligands endomorphin-1 and -2 in the mouse. Neurosci Lett 308: 17-20.[CrossRef][Medline]

Narita M, Ozaki S, and Suzuki T (2002) Endomorphin-induced motivational effect: differential mechanism of endomorphin-1 and endomorphin-2. Jpn J Pharmacol 89: 224-228.[CrossRef][Medline]

Negus SS, Henriksen SJ, Mattox A, Pasternak GW, Portoghese PS, Takemori AE, Weinger MB, and Koob GF (1993) Effect of antagonists selective for mu, delta and kappa opioid receptors on the reinforcing effects of heroin in rats. J Pharmacol Exp Ther 265: 1245-1252.[Abstract/Free Full Text]

Nestler EJ, Alreja M, and Aghajanian GK (1994) Molecular and cellular mechanisms of opiate action: studies in the rat locus coeruleus. Brain Res Bull 35: 521-528.[CrossRef][Medline]

Nevo I, Avidor-Reiss T, Levy R, Bayewitch M, and Vogel Z (2000) Acute and chronic activation of the µ-opioid receptor with the endogenous ligand endomorphin differentially regulates adenylyl cyclase isozymes. Neuropharmacology 39: 364-371.[CrossRef][Medline]

Nikolarakis KE, Almeida OFX, and Herz A (1987) Feedback inhibition of opioid peptide release in the hypothalamus of the rat. Neuroscience 23: 143-148.[CrossRef][Medline]

Nikulina EM, Hammer RP Jr, Miczek KA, and Kream RM (1999) Social defeat stress increases expression of µ-opioid receptor mRNA in rat ventral tegmental area. NeuroReport 10: 3015-3019.[Medline]

Nishimura E, Buchan AM, and McIntosh CH (1984) Autoradiographic localization of opioid receptors in the rat stomach. Neurosci Lett 50: 73-78.[CrossRef][Medline]

Nishimura E, Buchan AM, and McIntosh CH (1986) Autoradiographic localization of mu- and delta-type opioid receptors in the gastrointestinal tract of the rat and guinea pig. Gastroenterology 91: 1084-1094.[Medline]

Nishiwaki H, Saitoh N, Nishio H, Takeuchi T, and Hata F (1998) Relationship between inhibitory effect of endogenous opioid via mu-receptors and muscarinic autoinhibition in acetylcholine release from myenteric plexus of guinea pig ileum. Jpn J Pharmacol 77: 279-286.[CrossRef][Medline]

Nobre MJ, Ribeiro dos Santos N, Aguiar MS, and Brandao ML (2000) Blockade of µ- and activation of -opioid receptors in the dorsal periaqueductal gray matter produce defensive behavior in rats tested in the elevated plus-maze. Eur J Pharmacol 15: 145-151.[CrossRef]

North RA (1986) Opioid receptor types and membrane ion channels. Trends Neurosci 9: 114-117.[CrossRef]

Nozaki-Taguchi N and Yaksh TL (1999) Characterization of the antihyperalgesic action of a novel peripheral Mu-opioid receptor agonist Loperamide. Anesthesiology 90: 225-234.[CrossRef][Medline]

Nyberg F, Sanderson K, and Glamsta EL (1997) The hemorphins: a new class of opioid peptides derived from the blood protein hemoglobin. Biopolymers 43: 147-156.[CrossRef][Medline]

Obeso JA, Rodriguez-Oroz MC, Rodriguez M, DeLong MR, and Olanow CW (2000) Pathophysiology of levodopa-induced dyskinesias in Parkinson's disease: problems with the current model. Ann Neurol 47: S22-S34.[Medline]

Ohsawa M, Mizoguchi H, Narita M, Nagase H, Kampine JP, and Tseng LF (2001) Differential antinociception induced by spinally administered endomorphin-1 and endomorphin-2 in the mouse. J Pharmacol Exp Ther 298: 592-597.[Abstract/Free Full Text]

Okutsu H, Watanabe S, Takahashi I, Aono Y, Saigusa T, Koshikawa N, and Cools AR (2006) Endomorphin-2 and endomorphin-1 promote the extracellular amount of accumbal dopamine via nonopioid and mu-opioid receptors, respectively. Neuropsychopharmacology 31: 375-383.[CrossRef][Medline]

Olson GA, Olson RD, and Kastin AJ (1996) Endogenous opiates. Peptides 18: 1651-1688.[CrossRef]

Olson GA, Olson RD, Vaccarino AL, and Kastin AJ (1998) Endogenous opiates: 1997. Peptides 19: 1791-1843.[CrossRef][Medline]

Osterlund A, Arlander E, Eriksson LI, and Lindahl SGE (1999) The effects of resting ventilation of intravenous infusions of morphine or sameridine, a novel molecule with both local anesthetic and opioid properties. Anesth Analg 88: 160-165.[Abstract/Free Full Text]

Owen MD, Unal CB, Callahan MF, Triveldi K, York C, and Millington WR (2000) Glycyl-glutamine inhibits the respiratory depression, but not the antinociception, produced by morphine. Am J Physiol 279: R1944-R1948.

Owens NC, Sartor DM, and Verberne AJ (1999) Medial prefrontal cortex depressor response: role of the solitary tract nucleus in the rat. Neuroscience 89: 1331-1346.[CrossRef][Medline]

Passarelli F and Costa T (1989) Mu and delta opioid receptors inhibit serotonin release in rat hippocampus. J Pharmacol Exp Ther 248: 299-305.[Abstract/Free Full Text]

Pasternak GW (1993) Pharmacological mechanisms of opioid analgesic. Clin Neuropharmacol 16: 1-18.[Medline]

Patel HJ, Venkatesan P, Halfpenny J, Yacoub MH, Fox A, Barnes PJ, and Belvisi MG (1999) Modulation of acetylcholine release from parasympathetic nerves innervating guinea-pig and human trachea by endomorphin-1 and -2. Eur J Pharmacol 374: 21-24.[CrossRef][Medline]

Paterlini MG, Avitabile F, Ostrowski BG, Ferguson DM, and Portoghese PS (2000) Stereochemical requirements for receptor recognition of the µ-opioid peptide endomorphin-1. Biophys J 78: 590-599.[Medline]

Peckys D and Landwehrmeyer GB (1999) Expression of µ, , and -opioid receptor messenger RNA in the human CNS: a 35P in situ hybridization study. Neuroscience 88: 1093-1135.[CrossRef][Medline]

Pentney RJW and Gratton A (1991) Effects of local delta and mu opioid receptor activation on basal and stimulated dopamine release in striatum and nucleus accumbens of rat: an in vivo electrochemical study. Neuroscience 45: 95-102.[CrossRef][Medline]

Peoples JF, Wessendorf MW, Pierce T, and Van Bockstaele EJ (2002) Ultrastructure of endomorphin-1 immunoreactivity in the rat dorsal pontine tegmentum: evidence for preferential targeting of peptidergic neurons in Barrington's nucleus rather than catecholaminergic neurons in the peri-locus coeruleus. J Comp Neurol 448: 268-279.[CrossRef][Medline]

Peter A, Toth G, Tomboly C, Laus G, and Tourwe D (1999) Liquid chromatographic study of the enzymatic degradation of endomorphins, with identification by electrospray ionization mass spectrometry. J Chromatogr A 846: 39-48.[CrossRef][Medline]

Petersson M, Alster P, Lundeberg T, and Uvnas-Moberg K (1996) Oxytocin increases nociceptive thresholds in a long-term perspective in female and male rats. Neurosci Lett 212: 87-90.[CrossRef][Medline]

Petit-Demouliere B, Chenu F, and Bourin M (2005) Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology (Berl) 177: 245-255.[CrossRef][Medline]

Petty F, Kramer G, and Wilson L (1992) Prevention of learned helplessness: in vivo correlation with cortical serotonin. Pharmacol Biochem Behav 43: 361-367.[CrossRef][Medline]

Pfaff DW, Schwartz-Giblin S, McCarthy MM, and Kow L-M (1994) Cellular and molecular mechanisms of female reproductive behaviors, in The Physiology of Reproduction (Knobil E and Neill JD eds) vol 2, pp 107-220, Raven Press, New York.

Pfaus JG and Gorzalka BB (1987a) Opioids and sexual behavior. Neurosci Biobehav Rev 11: 1-34.[Medline]

Pfaus JG and Gorzalka BB (1987b) Selective activation of opioid receptors differentially affects lordosis behavior in female rats. Peptides 8: 309-317.[CrossRef][Medline]

Pfaus JG, Pendleton N, and Gorzalka BB (1986) Dual effect of morphiceptin on lordosis behavior: possible mediation by different opioid receptor subtypes. Pharmacol Biochem Behav 24: 1461-1464.[CrossRef][Medline]

Pfeiffer A and Herz A (1984) Endocrine actions of opioids. Horm Metab Res 16: 386-397.[Medline]

Piepponen TP, Kivastik T, Katajamaki J, Zharkovsky A, and Ahtee L (1997) Involvement of opioid µ1 receptors in morphine-induced conditioned place preference in rats. Pharmacol Biochem Behav 58: 275-279.[CrossRef][Medline]

Pierce TL, Grahek MD, and Wessendorf MW (1998) Immunoreactivity for endomorphin-2 occurs in primary afferents in rats and monkey. NeuroReport 9: 385-389.[Medline]

Pierce TL and Wessendorf MW (2000) Immunocytochemical mapping of endomorphin-2-immunoreactivity in rat brain. J Chem Neuroanat 18: 181-207.[CrossRef][Medline]

Pineda J, Torrecilla M, Martin-Ruiz R, and Ugedo L (1998) Attenuation of withdrawal-induced hyperactivity of locus coeruleus neurones by inhibitors of nitric oxide synthase in morphine-dependent rats. Neuropharmacology 37: 759-767.[CrossRef][Medline]

Pini LA, Vitale G, Ottani A, and Sandrini M (1997) Naloxone-reversible antinociception in the rat. J Pharmacol Exp Ther 280: 934-940.[Abstract/Free Full Text]

Podlogar BL, Paterlini MG, Ferguson DM, Leo GC, Demeter DA, Brown FK, and Reitz AB (1998) Conformational analysis of the endogenous mu-opioid agonist endomorphin-1 using NMR spectroscopy and molecular modeling. FEBS Lett 439: 13-20.[CrossRef][Medline]

Popik P, Mamczarz J, Fraczek M, Widla M, Hesselink M, and Danysz W (1998) Inhibition of reinforcing effects of morphine and naloxone-precipitated opioid withdrawal by novel glycine site and uncompetitive NMDA receptor antagonists. Neuropharmacology 37: 1033-1042.[CrossRef][Medline]

Porsolt RD, Bertin A, and Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229: 327-336.[Medline]

Potegal M, Huhman KL, Moore T, and Meyerhoff J (1993) Conditioned defeat in the Syrian hamster (Mesocricetus auratus). Behav Neural Biol 60: 93-102.[CrossRef][Medline]

Preston KL and Bigelow GE (2000) Effects of agonist-antagonist opioids in humans trained in a hydromorphone/not hydromorphone discrimination. J Pharmacol Exp Ther 295: 114-124.[Abstract/Free Full Text]

Proudfit HK (1988) Pharmacologic evidence for the modulation of nociception by noradrenergic neurones. Prog Brain Res 77: 357-370.[Medline]

Przewlocki R, Labuz D, Mika J, Przewlocka B, Tomboly C, and Toth G (1999) Pain inhibition by endomorphins. Ann NY Acad Sci 897: 154-164.[CrossRef][Medline]

Przewlocki R and Przewlocka B (2001) Opioids in chronic pain. Eur J Pharmacol 429: 79-91.[CrossRef][Medline]

Puig MM, Gascon P, Craviso GL, and Musacchio JM (1977) Endogenous opioid receptor ligand: electrically induced release in the guinea-pig ileum. Science (Wash DC) 195: 419-420.[Abstract/Free Full Text]

Pumford KM, Russell JA, and Leng G (1993) Effects of the selective -opioid agonist U50,488 upon the electrical activity of supraoptic neurones in morphine-tolerant and morphine-naive rats. Exp Brain Res 94: 237-246.[Medline]

Raab A, Dantzer R, Michaud B, Mormede P, Taghzouti K, Simon H, and LeMoal M (1986) Behavioural, physiological, and immunological consequences of social status and aggression in chronically coexisting resident-intruder dyads of male rats. Physiol Behav 36: 223-228.[CrossRef][Medline]

Ragozzino ME, Wenk GL, and Gold PE (1994) Glucose attenuates a morphine-induced decrease in hippocampal acetylcholine output: an in vivo microdialysis study in rats. Brain Res 655: 77-82.[CrossRef][Medline]

Reinscheid RK, Nothacker H-P, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ, and Civelli O (1995) Orphanin FQ: a novel neuropeptide which is a natural ligand of an opioid-like G protein-coupled receptor. Science (Wash DC) 270: 792-794.[Abstract/Free Full Text]

Reisine T and Pasternak GW (1996) Opioid analgesics and antagonists, in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Hardman JGL, Gilman A, and Limbird LE eds) pp 521-555, McGraw-Hill, New York.

Rialas CM, Fimiani C, Bilfinger TV, Salzet M, and Stefano GB (1998) Endomorphin-1 and -2 inhibit human vascular sympathetic norepinephrine release: lack of interaction with mu 3 opiate receptor subtype. Zhongguo Yao Li Xue Bao 19: 403-407.[Medline]

Ritzmann RF, Walter R, Bhargava HN, and Flexner LB (1979) Blockage of narcotic-induced dopamine receptor supersensitivity by cyclo(Leu–Gly). Proc Natl Acad Sci USA 76: 5997-5998.[Abstract/Free Full Text]

Robinson DA, Wei F, Wang GD, Li P, Kim SJ, Vogt SK, Muglia LJ, and Zhuo M (2002) Oxytocin mediates stress-induced analgesia in adult mice. J Physiol (Lond) 540: 593-606.[Abstract/Free Full Text]

Robinson TE and Becker JB (1986) Enduring changes in brain and behaviour produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res Rev 11: 157-198.[CrossRef]

Robinson TE and Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18: 247-291.[CrossRef][Medline]

Roche M, Commons KG, Peoples A, and Valentino RJ (2003) Circuitry underlying regulation of the serotonergic system by swim stress. J Neurosci 23: 970-977.[Abstract/Free Full Text]

Rockhold RW, Liu N, Coleman D, Commiskey S, Shook J, and Ho IK (2000) The nucleus paragigantocellularis and opioid withdrawal-like behavior. J Biomed Sci 7: 270-276.[CrossRef][Medline]

Rodgers RJ and Cole JC (1993) Anxiety enhancement in the murine elevated plus maze by immediate prior exposure to social stressors. Physiol Behav 53: 383-388.[CrossRef][Medline]

Rodriguez FD and Rodriguez RE (1989) Intrathecal administration of 5,6-DHT or 5,7-DHT reduced morphine and substance P antinociceptive activity in the rat. Neuropeptides 13: 139-146.[CrossRef][Medline]

Ronai AZ, Timar J, Mako E, Erdo F, Gyarmati Z, Toth G, Orosz G, Furst S, and Szekely JI (1999) Diprotin A, an inhibitor of dipeptidyl aminopeptidase IV (EC 3.4.14.5) produces naloxone-reversible analgesia in rats. Life Sci 64: 145-152.[Medline]

Rudy JW, Kuwagama K, and Pugh CR (1999) Isolation reduces contextual but not auditory-cue fear conditioning: a role for endogenous opioids. Behav Neurosci 113: 316-323.[CrossRef][Medline]

Russell JA, Leng G, and Bicknell RJ (1995) Opioid tolerance and dependence in the magnocellular oxytocin system: a physiological mechanism? Exp Physiol 80: 307-340.[Abstract]

Saha N, Datta H, and Sharma PL (1991) Effects of morphine on memory: interactions with naloxone, propranolol and haloperidol. Pharmacology 42: 10-14.[Medline]

Sakurada C, Sakurada S, Hayashi T, Katsuyama S, Tan-No K, and Sakurada T (2003) Degradation of endomorphin-2 at the supraspinal level in mice is initiated by dipeptidyl peptidase IV: an in vitro and in vivo study. Biochem Pharmacol 66: 653-661.[CrossRef][Medline]

Sakurada S, Hayashi T, and Yuhki M (2002) Differential antinociceptive effects induced by intrathecally-administered endomorphin-1 and endomorphin-2 in mice. Jpn J Pharmacol 89: 221-223.[CrossRef][Medline]

Sakurada S, Hayashi T, Yuhki M, Fujimura T, Murayama K, Yonezawa A, Sakurada C, Takeshita M, Zadina JE, Kastin AJ, et al. (2000) Differential antagonism of endomorphin-1 and endomorphin-2 spinal antinociception by naloxonazine and 3-methoxynaltrexone. Brain Res 881: 1-8.[CrossRef][Medline]

Sakurada S, Hayashi T, Yuhki M, Orito T, Zadina JE, Kastin AJ, Fujimura T, Murayama K, Sakurada C, Sakurada T, et al. (2001) Differential antinociceptive effects induced by intrathecally administered endomorphin-1 and endomorphin-2 in the mouse. Eur J Pharmacol 427: 203-210.[CrossRef][Medline]

Sakurada S, Zadina JE, Kastin AJ, Katsuyama S, Fujimura T, Murayama K, Yuki M, Ueda H, and Sakurada T (1999) Differential involvement of µ-opioid receptor subtypes in endomorphin-1-and -2-induced antinociception. Eur J Pharmacol 372: 25-30.[CrossRef][Medline]

Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, et al. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92: 573-585.[CrossRef][Medline]

Samini M, Fakhrian R, Mohagheghi M, and Dehpour AR (2000) Comparison of the effect of levodopa and bromocriptine on naloxone-precipitated morphine withdrawal symptoms in mice. Hum Psychopharmacol Clin Exp 15: 95-101.[CrossRef]

Sanchez-Blazquez P and Garzon J (1988) Pertussis toxin differentially reduces the efficacy of opioids to produce supraspinal analgesia in the mouse. Eur J Pharmacol 152: 357-361.[CrossRef][Medline]

Sanchez-Blazquez P, Rodriguez-Diaz M, DeAntonio I, and Garzon J (1999) Endomorphin-1, and endomorphin-2 show differences in their activation of µ-opioid receptor-regulated G proteins in supraspinal antinociception in mice. J Pharmacol Exp Ther 291: 12-18.[Abstract/Free Full Text]

Sante AB, Nobre MJ, and Brandao ML (2000) Place aversion induced by blockade of µ or activation of opioid receptors in the dorsal periaqueductal gray matter. Behav Pharmacol 11: 583-589.[Medline]

Saper B (1995) Central autonomic system, in The Rat Nervous System (Paxinos G ed) pp 107-135, Academic Press, New York.

Sapru HN (2002) Glutamate circuits in selected medullo-spinal areas regulating cardiovascular function. Clin Exp Pharmacol Physiol 29: 491-496.[CrossRef][Medline]

Sar M, Stumpf WE, Miller RJ, Chang KJ, and Cuatrecasas P (1978) Immunohistochemical localization of enkephalin in rat brain and spinal cord. J Comp Neurol 182: 17-37.[CrossRef][Medline]

Sasaki K, Fan LW, Tien LT, Ma T, Loh HH, and Ho IK (2002) The interaction of morphine and -aminobutyric acid (GABA)ergic systems in anxiolytic behavior: using mu-opioid receptor knockout mice. Brain Res Bull 57: 689-694.[CrossRef][Medline]

Sawynok J, Reid A, and Nance D (1991) Spinal antinociception by adenosine analogs and morphine after intrathecal administration of the neurotoxins capsaicin, 6-hydroxydopamine and 5,7-dihydroxytryptamine. J Pharmacol Exp Ther 258: 370-379.[Abstract/Free Full Text]

Sayin U, Atasoy S, Uzbay IT, Aricioglu-Kartal F, and Koyuncuoglu H (1998) Gamma-vinyl-GABA potentiates the severity of naloxone-precipitated abstinence signs in morphine-dependent rats. Pharmacol Res 38: 45-51.[CrossRef][Medline]

Sbrenna S, Marti M, Morari M, Calo' G, Guerrini R, Beani L, and Bianchi C (2000) Modulation of 5-hydroxytryptamine efflux from rat cortical synaptosomes by opioids and nociception. Br J Pharmacol 130: 425-433.[CrossRef][Medline]

Scarone S, Gambini O, Calabrese G, Sacerdote P, Bruni M, Carucci M, and Panerai AE (1990) Asymmetrical distribution of β-endorphin in cerebral hemispheres of suicides: preliminary data. Psychiatry Res 32: 159-166.[CrossRef][Medline]

Schildein S, Agmo A, Huston JP, and Schwarting RKW (1998) Intraaccumbens injections of substance P, morphine and amphetamine: effects on conditioned place preference and behavioral activity. Brain Res 790: 185-194.[CrossRef][Medline]

Schiller PW, Weltrowska G, Berezowska I, Nguyen TM, Wilkes BC, Lemieux C, and Chung NN (1999) The TIPP opioid peptide family: development of antagonists, agonists, and mixed µ agonist/ antagonists. Biopolymers 51: 411-425.[CrossRef][Medline]

Schreff M, Schulz S, Wiborny D, and Hollt V (1998) Immunofluorescent identification of endomorphin-2-containing nerve fibers and terminals in the rat brain and spinal cord. NeuroReport 9: 1031-1034.[Medline]

Schuh KJ, Walsh SL, and Stitzer ML (1999) Onset, magnitude and duration of opioid blockade produced by buprenorphine and naltrexone in humans. Psychopharmacology (Berl) 145: 162-174.[CrossRef][Medline]

Segal DM and Kuczenski R (1997) Repeated binge exposures to amphetamine and methamphetamine: behavioural and neurochemical characterization. J Pharmacol Exp Ther 282: 561-573.[Abstract/Free Full Text]

Shane R, Wilk S, and Bodnar RJ (1999) Modulation of endomorphin-2-induced analgesia by dipeptidyl peptidase IV. Brain Res 815: 278-286.[CrossRef][Medline]

Sharp BM, Roy S, and Bidlack JM (1998) Evidence for opioid receptors on cells involved in host response and the immune system. J Neuroimmunol 83: 45-56.[CrossRef][Medline]

Shen J, Gomes B, Gallagher A, Stafford K, and Yoburn BC (2000) Role of cAMP-dependent protein kinase (PKA) in opioid agonist-induced µ-opioid receptor down-regulation and tolerance in mice. Synapse 38: 322-327.[CrossRef][Medline]

Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, et al. (2003) Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 54: 70-75.[CrossRef][Medline]

Shirayama Y, Chen AC, Nakagawa S, Russell DS, and Duman RS (2002) Brain-derived neurotrophic factor produces antidepressant effects in behavioral model of depression. J Neurosci 22: 3251-3261.[Abstract/Free Full Text]

Shook J, Watkins W, and Camporesi E (1990) Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression. Am Rev Respir Dis 142: 895-909.[Medline]

Silverman MB, Hermes SM, Zadina JE, and Aicher SA (2005) Mu-opioid receptor is present in dendritic targets of endomorphin-2 axon terminals in the nuclei of the solitary tract. Neuroscience 135: 887-896.[CrossRef][Medline]

Sim LJ, Liu Q, Childers SR, and Selley DE (1998) Endomorphin-stimulated [³⁵S]GTPS binding in rat brain: evidence for partial agonist activity at µ-opioid receptors. J Neurochem 70: 1567-1576.[Medline]

Simantov R, Kuhar MJ, Uhl GR, and Snyder SH (1977) Opioid peptide enkephalin: immunohistochemical mapping in rat central nervous system. Proc Natl Acad Sci USA 74: 2167-2171.[Abstract/Free Full Text]

Simpson KL, Altman DW, Wang L, Kirifides ML, Lin RC, and Waterhouse BD (1997) Lateralization and functional organization of the locus coeruleus projection to the trigeminal somatosensory pathway in rat. J Comp Neurol 385: 135-147.[CrossRef][Medline]

Sinchak K and Micevych PE (2001) Progesterone blockade of estrogen activation of µ-opioid receptors regulates reproductive behaviour. J Neurosci 21: 5723-5729.[Abstract/Free Full Text]

Sirinathsinghji DJ (1984) Modulation of lordosis behavior of female rats by naloxone, β-endorphin and its antiserum in the mesencephalic central gray: possible mediation via GnRH. Neuroendocrinology 39: 222-230.[Medline]

Sirinathsinghji DJ (1985) Modulation of lordosis behaviour in the female rat by corticotropin releasing factor, β-endorphin and gonadotropin releasing hormone in the mesencephalic central gray. Brain Res 336: 45-55.[CrossRef][Medline]

Sirinathsinghji DJ (1986) Regulation of lordosis behaviour in the female rat by corticotropin-releasing factor, β-endorphin/corticotrophin and luteinizing hormone-releasing hormone neuronal systems in the medial preoptic area. Brain Res 375: 49-56.[CrossRef][Medline]

Siuciak JA, Lewis DR, Wiegand SJ, and Lindsay RM (1997) Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 56: 131-137.[CrossRef][Medline]

Sleigh JW (1999) Postoperative respiratory arrhythmias: incidence and measurement. Acta Anaesthesiol Scand 43: 708-714.[CrossRef][Medline]

Smith CB, Sheldon MI, Bednarczyk JH, and Villarreal JE (1972) Morphine-induced increases in the incorporation of ¹⁴C-tyrosine into ¹⁴C-dopamine and ¹⁴C-norepinephrine in the mouse brain: antagonism by naloxone and tolerance. J Pharmacol Exp Ther 180: 547-557.[Abstract/Free Full Text]

Spampinato S, Qasem AR, Calienni M, Murari G, Gentilucci L, Tolomelli A, and Cardillo G (2003) Antinociception by a peripherally administered novel endomorphin-1 analogue containing β-proline. Eur J Pharmacol 469: 89-95.[CrossRef][Medline]

Spanagel R (1995) Modulation of drug-induced sensitization processes by endogenous opioid systems. Behav Brain Res 70: 37-49.[CrossRef][Medline]

Spanagel R, Herz A, and Shippenberg TS (1990) The effects of opioid peptides on dopamine release in the nucleus accumbens: an in vivo microdialysis study. J Neurochem 55: 1734-1740.[Medline]

Spanagel R, Herz A, and Shippenberg TS (1992) Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci USA 89: 2046-2050.[Abstract/Free Full Text]

Spanagel R, Sillaber I, Zieglgansberger W, Corrigall WA, Stewart J, and Shaham Y (1998) Acamprosate suppresses the expression of morphine-induced sensitization in rats but does not affect heroin self-administration or relapse induced by heroin or stress. Psychopharmacology (Berl) 139: 391-401.[CrossRef][Medline]

Spetea M, Monory K, Tomboly C, Toth G, Tzavara E, Benyhe S, Hanoune J, and Borsodi A (1998) In vitro binding and signaling profile of the novel µ opioid receptor agonist endomorphin 2 in rat brain membranes. Biochem Biophys Res Commun 250: 720-725.[CrossRef][Medline]

Spinella M, Cooper ML, and Bodnar RJ (1996) Excitatory amino acid antagonists in the rostral ventromedial medulla inhibit mesencephalic morphine analgesia in rats. Pain 64: 545-552.[CrossRef][Medline]

Spreekmeester E and Rochford J (2000) Selective mu and delta, but not kappa, opiate receptor antagonists inhibit the habituation of novelty-induced hypoalgesia in the rat. Psychopharmacology (Berl) 148: 99-105.[CrossRef][Medline]

Spyraki C, Fibinger HC, and Phillips AG (1983) Attenuation of heroin reward in rats by disruption of the mesolimbic dopamine system. Psychopharmacology (Berl) 79: 278-283.[CrossRef][Medline]

Stanley BG, Lanthier D, and Leibowitz SF (1988) Multiple brain sites sensitive to feeding stimulation by opioid agonists: a cannula-mapping study. Pharmacol. Biochem. Behav 31: 825-832.[CrossRef][Medline]

Starke K (1977) Regulation of noradrenaline release by presynaptic receptor systems. Rev Physiol Biochem Pharmacol 7: 1-124.

Stewart J and Badiani A (1993) Tolerance and sensitization to the behavioral effects of drugs, Behav Pharmacol 4: 289-312.[Medline]

Stinus L, Robert C, Karasinski P, and Limoge A (1998) Continuous quantitative monitoring of spontaneous opiate withdrawal: locomotor activity and sleep disorders. Pharm Biochem Behav 59: 83-89.[CrossRef][Medline]

Stoll AL and Rueter S (1999) Treatment augmentation with opiates in severe and refractory major depression. Am J Psychiatry 156: 2017.[Free Full Text]

Stone LS, Fairbanks CA, Laughlin TM, Nguyen HO, Bushy TM, Wessendorf MW, and Wilcox GL (1997) Spinal analgesic actions of the new endogenous opioid peptides endomorphin-1 and -2. NeuroReport 8: 3131-3135.[Medline]

Storr M, Gaffal E, Schusdziarra V, and Allescher HD (2002a) Endomorphins 1 and 2 reduce relaxant non-adrenergic, non-cholinergic neurotransmission in rat gastric fundus. Life Sci 71: 383-389.[CrossRef][Medline]

Storr M, Geisler F, Neuhuber WL, and Allescher HD (2000a) Autonomic modulation of vagal input to the rat esophageal muscle: Influence of opiates, in Neurogastroenterology: From the Basics to the Clinics (Krammer HJ and Singer MV eds), Kluwer Academic Publishers, London.

Storr M, Geisler F, Neuhuber WL, Schusdziarra V, and Allescher HD (2000b) Endomorphin 1 and 2, endogenous ligands for the µ-opioid receptor, inhibit striated and smooth muscle contraction in the rat esophagus. Neurogastroenterol Motil 12: 441-448.[CrossRef][Medline]

Storr M, Hahn A, Gaffal E, Saur D, and Allescher HD Effects of endomorphin-1 and -2 on µ-opioid receptors in myenteric neurons and in the peristaltic reflex in rat small intestine Clin Exp Pharmacol Physiol 29: 428-434, 2002b.[CrossRef][Medline]

Su R-B, Li J, Gao K, Pei G, and Qin B-Y (2000) Influence of idazoxan on analgesia, tolerance, and physical dependence of morphine in mice and rats in vivo. Acta Pharmacol Sin 21: 1011-1015.[Medline]

Sugimoto-Watanabe A, Kubota K, Fujibayashi K, and Saito K (1999) Antinociceptive effect and enzymatic degradation of endomorphin-1 in newborn rat spinal cord. Jpn J Pharmacol 81: 264-270.[CrossRef][Medline]

Suh HH, Fujimoto JM, and Tseng LF (1989) Differential mechanisms mediating β-endorphin- and morphine-induced analgesia in mice. Eur J Pharmacol 168: 61-79.[CrossRef][Medline]

Suh HH, Hong JJ-S, and Tseng LF (1992) Intrathecal DSP-4,6-hydroxydopamine and 5,7-dihydroxytryptamine differentiate intracerebroventricular β-endorphin- from morphine-induced antinociception in the mouse. Pharmacol Commun 1: 227-232.

Sun SY, Liu Z, Li P, and Ingenito AJ (1996) Central effects of opioid agonists and naloxone on blood pressure and heart rate in normotensive and hypertensive rats. Gen Pharmacol 27: 1187-1194.[Medline]

Sutin EL and Jacobowitz DM (1988) Immunocytochemical localization of peptides and other neurochemicals in the rat laterodorsal tegmental nucleus and adjacent area. J Com Neurol 270: 243-270.[CrossRef][Medline]

Suzuki T (1996) Conditioned place preference in mice. Methods Find Exp Clin Pharmacol 18: 75-83.

Swanson LW (1987) The hypothalamus, in Handbook of Chemical Neuroanatomy (Bjorklund A, Hokfelt T, and Swanson LW eds) pp 1-104, Elsevier, New York.

Szatmari I, Biyashev D, Tomboly C, Toth G, Macsai M, Szabo G, Borsodi A, and Lengyel I (2001) Influence of degradation on binding properties and biological activity of endomorphin-1. Biochem Biophys Res Commun 284: 771-776.[CrossRef][Medline]

Szekely JI and Ronai AZ (1982a) Opioid Peptides, vol I: Research Methods, CRC Press, Boca Raton, FL.

Szekely JI and Ronai AZ (1982b) Opioid Peptides, vol II: Pharmacology. CRC Press, Boca Raton, FL.

Takahashi M, Fukunaga H, Kaneto H, Fukodome S, and Yoshikawa M (2000) Behavioral and pharmacological studies on gluten exorphin A5, a newly isolated bioactive food protein fragment, in mice. Jpn J Pharmacol 84: 259-265.[CrossRef][Medline]

Takita K, Herlenius E, Lindahl SGE, and Yamamoto Y (1998) Age- and temperature-dependent effects of opioids on medulla oblongata respiratory activity: an in vitro study in newborn rat. Brain Res 800: 308-311.[CrossRef][Medline]

Takita K, Herlenius E, Yamamoto Y, and Lindahl SGE (2000) Effects of neuroactive substances on the morphine-induced respiratory depression: an in vitro study. Brain Res 884: 201-205.[CrossRef][Medline]

Tao R and Auerbach SB (1995) Involvement of the dorsal raphe but not median raphe nucleus in morphine-induced increases in serotonin release in the rat forebrain. Neuroscience 68: 553-561.[CrossRef][Medline]

Tao R and Auerbach SB (2002) Opioid receptor subtypes differentially modulate serotonin efflux in the rat central nervous system. J Pharmacol Exp Ther 303: 549-556.[Abstract/Free Full Text]

Tao R, Ma Z, and Auerbach SB (1996) Differential regulation of 5-hydroxytryptamine release by GABAA and GABAB receptors in midbrain raphe nuclei and forebrain of rats. Br J Pharmacol 119: 1375-1384.[Medline]

Tejedor-Real P, Mico JA, Maldonado R, Roquest BP, and Gibert-Rahola J (1995) Implication of endogenous opioid system in the learned helplessness model of depression. Pharmacol Biochem Behav 52: 145-152.[CrossRef][Medline]

Tejwani GA, Sheu M-J, Sribanditmongkol P, and Satyapriya A (1998) Inhibition of morphine tolerance and dependence by diazepam and its relation to m-opioid receptors in the rat brain and spinal cord. Brain Res 797: 305-312.[CrossRef][Medline]

Teppema L, Sarton E, Dahan A, and Olievier CN (2000) The neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) and morphine act independently on the control of breathing. Br J Anaesth 84: 190-196.[Abstract/Free Full Text]

Ter Horst GJ, De Boer P, Luiten PGM, and Van Willigen JD (1989) Ascending projections from the solitary tract nucleus to the hypothalamus: a Phaseolus vulgaris lectin tracing study in the rat. Neuroscience 31: 785-797.[CrossRef][Medline]

Thornton SR and Smith FL (1998) Long-term alterations in opiate antinociception resulting from infant fentanyl tolerance and dependence. Eur J Pharmacol 363: 113-119.[CrossRef][Medline]

Tokuyama S, Ho IK, and Yamamoto T (2000) A protein kinase inhibitor, H-7, blocks naloxone-precipitated changes in dopamine, and its metabolites in the brains of opioid-dependent rats. Brain Res Bull 52: 363-369.[CrossRef][Medline]

Tomboly C, Peter A, and Toth G (2002) In vitro quantitative study of the degradation of endomorphins. Peptides 23: 1573-1580.[CrossRef][Medline]

Tonini M, Fiori E, Balestra B, Spelta V, D'Agostino G, Di Nucci A, Brecha NC, and Sternini C (1998) Endomorphin-1 and endomorphin-2 activate µ-opioid receptors in myenteric neurons of the guinea-pig small intestine. Naunyn-Schmiedeberg's Arch Pharmacol 358: 686-689.[CrossRef][Medline]

Torii M and Kubo K (1994) The effects of intraventricular injection of β-endorphin on initial estrogen action to induce lordosis behavior. Physiol Behav 55: 157-162.[CrossRef][Medline]

Torii M, Kubo K, and Sasaki T (1997) Differential effects of β-endorphin and Met- and Leu-enkephalin on steroid hormone-induced lordosis in ovariectomized female rats. Pharmacol Biochem Behav 58: 837-842.[CrossRef][Medline]

Torii M, Kubo K, and Sasaki T (1999) Facilitatory and inhibitory effects of β-endorphin on lordosis in female rats: relation to time of administration. Neurosci Lett 276: 177-180.[CrossRef][Medline]

Torrealba F and Müller C (1996) Glutamate immunoreactivity of insular cortex afferents to the nucleus tractus solitarius in the rat: a quantitative electron microscopic study. Neuroscience 71: 77-87.[CrossRef][Medline]

Tseng LF (2002) Recent advances in the search for the µ-opioidergic system—the antinociceptive properties of endomorphin-1 and endomorphin-2 in the mouse. Jpn J Pharmacol 89: 216-220.[CrossRef][Medline]

Tseng LF and Collins KA (1991) Different mechanisms mediating tail-flick inhibition induced by β-endorphin, DAMGO and morphine form Rob and GiA in anesthetized rat. J Pharmacol Exp Ther 257: 530-538.[Abstract/Free Full Text]

Tseng LF, Narita M, Suganuma C, Mizoguchi H, Ohsawa M, Nagase H, and Kampine JP (2000) Differential antinociceptive effects of endomorphin-1 and endomorphin-2 in the mouse. J Pharmacol Exp Ther 292: 576-583.[Abstract/Free Full Text]

Tseng LF and Tang R (1990) Differential mechanisms mediate β-endorphin- and morphine-induced inhibition of the tail-flick response in rats. J Pharmacol Exp Ther 252: 546-551.[Abstract/Free Full Text]

Tsuda M, Suzuki T, Misawa M, and Nagase H (1996) Involvement of the opioid system in the anxiolytic effect of diazepam in mice. Eur J Pharmacol 307: 7-14.[CrossRef][Medline]