Neurochemical and morphological evidence of an antinociceptive neural pathway from nucleus raphe dorsalis to nucleus accumbens in the rabbit

doi:10.1016/0361-9230(92)90215-J

Brain Research Bulletin

Volume 28, Issue 6, June 1992, Pages 931-936

https://doi.org/10.1016/0361-9230(92)90215-J Get rights and content

Abstract

Previous studies using a pharmacological approach suggested a neural pathway emanating from the periaqueductal gray (PAG) to the nucleus accumbens relevant to antinociception. This was investigated with neurochemical and histochemical methods in the present study. Push-pull perfusion and radioimmunoassay were used to measure the release of immunoreactive-(ir) enkephalin (ir-ENK) and ir-β-endorphin (ir-β-EP) in the nucleus accumbens after microinjection of morphine into the PAG and the nucleus raphe dorsalis (NRD) of the rabbit. Morphine administration elicited an increase in ir-ENK and ir-β-EP in the nucleus accumbens. Horseradish peroxidase (HRP) retrograde tracing in combination with 5-hydroxytryptamine (5-HT) immunocytochemistry revealed a serotonergic projection from the NRD and ventral PAG to the nucleus accumbens in the rabbit. About 7% of the serotonin-positive cells in the NRD and ventral PAG send fibers directly to the nucleus accumbens, with an ipsilateral dominance. These results indicate the existence of a serotonergic pathway from the NRD to the N, accumbens involved in opioid analgesia.

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In particular, the hippocampus (HIPP)-nucleus accumbens (NAC) pathway with its interplay between 5-HT and DA plays a crucial role in the mediation of psychoactive drug use and addiction (for review see Müller and Homberg, 2015). The rostral raphe nuclei of the brainstem provide vast 5-HTergic innervation to the regions of the nigrostriatal (substantia nigra [SN], Wirtshafter et al., 1987; caudateputamen [CP], Steinbusch et al., 1980; globus pallidus [GP], Eid and Parent, 2016; subthalamic nucleus, Carpenter et al., 1981; thalamus [THAL], Moore et al., 1978) and mesolimbocortical DAergic system (ventral tegmental area [VTA], Oades and Halliday, 1987; NAC, Ma and Han, 1992; HIPP, Köhler and Steinbusch, 1982; amygdala [AMYG], Köhler and Steinbusch, 1982; neocortex, Kievit and Kuypers, 1975). Neurochemical studies indicate that 5-HT modulates the release of DA (Matsumoto et al., 1999), while DA, in turn, modulates the release of 5-HT (Matsumoto et al., 1996).
Serotonin(5-HT)ergic projections run from the raphe nuclei to dopamin(DA)ergic cells in substantia nigra/ventral tegmental area (SN/VTA) and to the terminal fields of DA neurons in nucleus accumbens, caudateputamen and neocortex. In the present studies, we assessed the effect of the 5-HT_1A receptor (R) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarbox-amide maleate (WAY-100635) on motor and exploratory behaviors and on D_2/3R binding in the rat brain with in vivo imaging methods. D_2/3R binding was determined in the same animals after systemic application of WAY-100635 (0.4 mg/kg) and 0.9% saline (SAL), respectively, with [¹²³I]IBZM as SPECT ligand. Anatomical information for the delineation of the target regions was obtained with dedicated small animal MRI. Immediately after treatment with WAY-100635 or SAL, motor/exploratory behaviors were assessed for 30 min in two different batches of animals in an open field. WAY-100635 reduced D_2/3R binding in caudateputamen, thalamus, frontal cortex, parietal cortex and ventral hippocampus relative to SAL. Network analysis of regional binding data after WAY-100635 yielded positive connections between (1) caudateputamen and substantia nigra/ventral tegmental area, (2) caudateputamen and ventral hippocampus, (3) substantia nigra/ventral tegmental area and parietal cortex, (4) thalamus and dorsal hippocampus and (5) frontal cortex and parietal cortex, which were not present after SAL. Moreover, WAY-100635 decreased parameters of motor activity (overall activity, ambulation duration and frequency) but increased the duration of grooming behavior relative to SAL. The effect on exploration was time-dependent with an early increase and a subsequent decrease of behavioral parameters (rearing duration and frequency, frequency of head-shoulder motility). For WAY-100635, findings imply a region-specificity as well as a time-dependency of DAergic action.
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Similarly, serotonin receptors are present in primary afferent terminals and interneurons facilitating or inhibiting nociceptive transmission depending on the receptor subtype. For instance, noxious stimuli activate opioidergic neurons in the PAG, which in turn modulate serotonergic projections to supraspinal nuclei including the nucleus accumbens and amygdala (Ma and Han, 1992; Grahn et al., 1999). In addition, morphine administration increases serotonin in the spinal cord (Kimura et al., 2014).
Opioid-sparing adjuncts are treatments that aim to reduce the overall dose of opioids needed to achieve analgesia, hence decreasing the burden of side effects through alternative mechanisms of action. Lorcaserin is a serotonin 5-HT_2C receptor (5-HT_2CR) agonist that has recently been reported to reduce abuse-related effects of the opioid analgesic oxycodone. The goal of our studies was to evaluate the effects of adjunctive lorcaserin on opioid-induced analgesic-like behavior using the tail-flick reflex (TFR) test as a mouse model of acute thermal nociception. We show that whereas subcutaneous (s.c.) administration of lorcaserin alone was inactive on the TFR test, adjunctive lorcaserin (s.c.) significantly increased the potency of oxycodone as an antinociceptive drug. This effect was prevented by the 5-HT_2CR antagonist SB242084. A similar lorcaserin (s.c.)-induced adjunctive phenotype was observed upon administration of the opioid analgesics morphine and fentanyl. Remarkably, we also show that, opposite to the effects observed via s.c. administration, intrathecal (i.t.) administration of lorcaserin alone induced antinociceptive TFR behavior, an effect that was not prevented by the opioid receptor antagonist naloxone. This route of administration (i.t.) also led to a significant augmentation of oxycodone-induced antinociception. Lorcaserin (s.c.) did not alter the brain or blood concentrations of oxycodone, which suggests that its adjunctive effects on opioid-induced antinociception do not depend upon changes in opioid metabolism. Together, these data indicate that lorcaserin-mediated activation of the 5-HT_2CR may represent a new pharmacological approach to augment opioid-induced antinociception.
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Injections into the DRN of morphine inhibited the spinal nociceptive reflex [131], and injections of 5-hydroxytryptophan, a precursor of 5-HT raised pain thresholds [132]. These analgesic effects in the DRN were attributed to the activity of neurons that contain 5-HT and enkephalin [133,134], while GABA neurons in the DRN appear to have the opposite effect on pain [135], presumably because they inhibit 5-HT neurons [27]. It is plausible that the LHb–DRN pathway is involved in pain modulation because of their known individual roles in mediating pain responses and their anatomical connections [16].
Serotonergic neurons in the dorsal raphe nucleus (DRN) play an important role in regulation of many physiological functions. The lateral nucleus of the habenular complex (LHb) is closely connected to the DRN both morphologically and functionally. The LHb is a key regulator of the activity of DRN serotonergic neurons, and it also receives reciprocal input from the DRN. The LHb is also a major way-station that receives limbic system input via the stria medullaris and provides output to the DRN and thereby indirectly connects a number of other brain regions to the DRN. The complex interactions of the LHb and DRN contribute to the regulation of numerous important behavioral and physiological mechanisms, including those regulating cognition, reward, pain sensitivity and patterns of sleep and waking. Disruption of these functions is characteristic of major psychiatric illnesses, so there has been a great deal of interest in how disturbed LHb–DRN interactions may contribute to the symptoms of these illnesses. This review summarizes recent research related to the roles of the LHb–DRN system in regulation of higher brain functions and the possible role of disturbed LHb–DRN function in the pathogenesis of psychiatric disorders, especially depression.
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Together, these data suggest that the antinociceptive effect of morphine in the DRN is mediated by μ-opioids receptors, and there is no tonic releasing of opioids in the DRN. The antinociception induced by the microinjection of morphine into the DRN depends on the activation of the many projections from DRN identified as 5-HT, including projections to regions that were recognized to be involved in pain perception and pain modulation (Petrov et al., 1992; Ma and Han, 1992; Huo et al., 2008). Since the effect of the morphine on the μ-opiate receptors is inhibitory (Duggan and North, 1983; Pan et al., 1990), the antinociception by morphine application might be due to the inhibition of the tonically active GABAergic interneurons into DRN.
The dorsal raphe nucleus (DRN) is involved in the control of several physiological functions, including nociceptive modulation. This nucleus is one of the main sources of serotonin to the CNS and neuromodulators such as opioids and GABA may be are important for its release. This study evaluated the influence of serotonergic, GABAergic and opioidergic stimulation, as well as their interactions in the DRN, on vocalization nociceptive response during a peripheral noxious stimulus application in guinea pigs. Morphine (1.1 nmol), bicuculline (0.50 nmol) and alpha-methyl-5-HT (1.6 nmol) microinjection on the DRN produces antinociception. The antinociception produced by morphine (1.1 nmol) and alpha-methyl-5-HT (1.6 nmol) into the DRN was blocked by prior microinjection of naloxone (0.7 nmol). The alpha-methyl-5-HT effect blocked by naloxone may indicate the existence of 5-HT_2A receptors on enkephalinergic interneurons within the dorsal raphe. Pretreatment with muscimol (0.26 nmol) also prevented the antinociceptive effect caused by morphine (1.1 nmol) when administered alone at the same site, indicating an interaction between GABAergic and opioidergic interneurons. The antinociception produced by bicuculline (0.5 nmol) in the DRN was blocked by prior administration of 8-OH-DPAT (0.5 nmol), a 5-HT_1A agonist. This may indicate that the 5-HT autoreceptor activation by 8-OH-DPAT at DRN effector neurons can oppose the bicuculline disinhibition effect applied to the same effectors. Thus, we suggest that 5-HT₂ receptor activation in the DRN promotes endorphin/enkephalin release that may disinhibit efferent serotonergic neurons of this present structure by inhibiting GABAergic interneurons, resulting in antinociception.
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Crotoxin (CTX), a neurotoxin isolated from the venom of the South American rattlesnake Crotalus durissus terrificus, induces analgesia. In this study, we evaluated the antinociceptive effect of CTX in a model of neuropathic pain induced by rat sciatic nerve transection. Hyperalgesia was detected 2 h after nerve transection and persisted for 64 days. Immersion of proximal and distal nerve stumps in CTX solution (0.01 mM for 10 s), immediately after nerve transection, blocked hyperalgesia. The antinociceptive effect of CTX was long-lasting, since it was detected 2 h after treatment and persisted for 64 days. CTX also delayed, but did not block, neurectomy-induced neuroma formation. The effect of CTX was blocked by zileuton (100 mg/kg, p.o.) and atropine (10 mg/kg, i.p.), and reduced by yohimbine (2 mg/kg, i.p.) and methysergide (5 mg/kg, i.p.). On the other hand, indomethacin (4 mg/kg, i.v.), naloxone (1 mg/kg, i.p.), and N-methyl atropine (30 mg/kg, i.p.) did not interfere with the effect of CTX. These results indicate that CTX induces a long-lasting antinociceptive effect in neuropathic pain, which is mediated by activation of central muscarinic receptors and partially, by activation of α-adrenoceptors and 5-HT receptors. Eicosanoids derived from the lipoxygenase pathway modulate the action of crotoxin.
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A comprehensive fiber connects the dorsal raphe nucleus and many functional nuclei in the brain. It has been reported that serotonergic projective fibers extend from the dorsal raphe nucleus to the midbrain periaqueductal gray matter (PAG), the superior colliculus [3], the arcuate nucleus, the ventromedial hypothalamic region [51], the septal area [25], the parafascicular nucleus [8,34], the ventral posterolateral nucleus [50], the amygdalae nucleus [14,28], the accumbens septal nucleus [27], the rostroventrolateral medulla [1] and the somatosensory cortices [4]. Using the HRP tracing method [30,41], Marchand and Saka et al. found that the neurons in the dorsal raphe nucleus received a lot of axis-cylinder contact from many regions of the brain.
Many studies have been made on the distributions of CSF contacting neurons (CSF-CNs) in the parenchyma of the brain with horseradish peroxidase (HRP) or autoradiographics. A significant amount of data has shown that both HRP and autoradiographical substances could pass freely through the spaces of ependyma into the parenchyma of the brain. It is therefore possible that the results were not exact. We found that CB-HRP was a dependable tracer to CSF-CNs and studied the distributions and the signaling directions of cerebrospinal fluid contacting neurons (CSF-CNs) in the parenchyma of the brain with the cholera toxin subunit B with horseradish peroxidase (CB-HRP) tracing combined with transmission electron microscopy. The results were as follows: (1) CSF contacting tanycytes existed not only in the wall of the third ventricle (3V), but also in the walls of the lateral ventricle (LV), the fourth ventricle (4V) and the central canal (CC) of the spinal cord. (2) Some CSF contacting glia cells were observed in the lateral septal nucleus (LS). (3)The distal CSF-CNs in the parenchyma were found in LS, the anterodorsal thalamic nucleus (AD), the supramammillary nucleus (SuM), the dorsal raphe nucleus (DR), the floor of 4V and the lateral superior olive (LSO), but they were mainly found in DR and divided into groups A and B. (4) Axon terminals labeled by CB-HRP were found in the cavity of the brain ventricle. (5) The synaptic relationships between the neurons were labeled by CB-HRP in DR and no-labeled by CB-HRP in the parenchyma. Both synapses Gray I and II were found. It was significant that the presynaptic elements were formed by the neurons no-labeled CB-HRP and the postsynaptic elements labeled CB-HRP. Our results suggested firstly that the signaling directions of CSF-CNs in DR were only from the parenchyma to CSF.

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Brief communicationNeurochemical and morphological evidence of an antinociceptive neural pathway from nucleus raphe dorsalis to nucleus accumbens in the rabbit

Abstract

Brain Res.

Neuropharmacology

Brain Res.

Brain Res.

Neuropharmacology

Trends Neurosci.

Neurosci. Lett.

Neuroscience

Brain Res.

Neuroscience

An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat

J. Comp. Neurol.

Connections of the median and dorsal raphe nuclei in the rat: An autoradiographic and degeneration study

J. Comp. Neurol.

The effect of microinjection of naloxone into nucleus accumbens on acupuncture analgesia in the rat

J. Beijing Med. Univ.

The raphe nuclei of the rabbit brain stem

J. Comp. Neurol.

A mesolimbic loop of analgesia.I. Activation by morphine of a serotonergic pathway from periaqueductal gray to nucleus accumbens

Int. J. Neurosci.

Brief communication
Neurochemical and morphological evidence of an antinociceptive neural pathway from nucleus raphe dorsalis to nucleus accumbens in the rabbit