Analgesic tolerance and cross-tolerance to i.c.v. endomorphin-1, endomorphin-2, and morphine in mice

doi:10.1016/j.neulet.2004.05.046

Neuroscience Letters

Volume 366, Issue 2, 12 August 2004, Pages 211-214

https://doi.org/10.1016/j.neulet.2004.05.046 Get rights and content

Abstract

The present study examined the development of analgesic tolerance to endomorphin-1 (EM1), endomorphin-2 (EM2), and morphine, and cross-tolerance among these drugs. Male Swiss Webster mice were injected i.c.v. with EM1, EM2, morphine, or vehicle once daily for 5 days, and tested for analgesia in the tail flick test. To determine the extent of cross-tolerance, on the sixth day mice from each of the above groups received i.c.v. injections of EM1, EM2, morphine, or vehicle before analgesic testing. The development of tolerance to EM1 and EM2 closely resembled that of morphine. Complete, symmetrical cross-tolerance was observed between all drugs in the study. These results demonstrate a time-course and extent of tolerance similar to morphine, and support a common mechanism of action through the mu-opioid receptor.

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Acknowledgements

Supported by the University of New Orleans, the Veterans Affairs Administration (Merit Review and MIRECC) and the Louisiana State Board of Regents.

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Analgesic tolerance and cross-tolerance to the bifunctional opioid/neuropeptide FF receptors agonist EN-9 and μ-opioid receptor ligands at the supraspinal level in mice
2023, Neuropeptides
Citation Excerpt :
The above findings of differences between the cross-tolerance of EN-9 and morphine suggest that chronic injection of EN-9 may lead to the downstream μ-mediated pathway participating, consistent with previous studies that κ- and μ-opioid receptors interact with each in chronic treatment (Yamada et al., 2006; Li et al., 2010). Additionally, the observation of symmetrical but not complete cross-tolerance between 60 nmol EM2 and 30 nmol morphine in this study was consistent with the findings of previous investigation (Soignier et al., 2004). Furthermore, previous studies demonstrated that co-injection of RF9 with EN-9 produced a stage-wise loss of analgesia and developed significant tolerance after repeated injections, and antinociception recovered after the removal of RF9, implying the important role of the activation of NPFF receptor in reducing the development of tolerance to EN-9 (Wang et al., 2016).
The chimeric peptide EN-9 was reported as a κ-opioid/neuropeptide FF receptors bifunctional agonist that modulated chronic pain with no tolerance. Many lines of evidence have shown that the effect of the κ-opioid receptor is mediated by not only its specific activation but also downstream events participation, especially interaction with the μ-opioid receptor pathway in antinociception and tolerance on most occasions. The present study investigated the acute and chronic cross-tolerance of EN-9 with μ-opioid receptor agonist EM-2, DAMGO, and morphine after intracerebroventricularly (i.c.v) injection in the mouse tail-flick test. In the acute tolerance test, EN-9 showed symmetrical acute cross-tolerance to DAMGO but no cross-tolerance to EM2. In the chronic tolerance test, EN-9 had no tolerance after eight days of repeated administration. However, EN-9 illustrated complete cross-tolerance to morphine and symmetrical cross-tolerance to EM2. In addition, inhibition of NPFF receptor could induce the tolerance development of EN-9. These findings indicated that supraspinal EN-9-induced antinociception contains additional components, which are mediated by the downstream μ-opioid receptor pathway both in acute and chronic treatment, whereas the subtypes of μ-opioid receptor or NPFF system pathway involved in antinociceptive effects induced by EN-9 are complex. Identifying the receptor mechanism could help design preferable bifunctional opioid compounds.
Morphological features of endomorphin-2-immunoreactive ultrastructures in the dorsal root ganglion and spinal dorsal horn of the rat
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Citation Excerpt :
These EM2-ir fibers and terminals play important roles in modulating nociceptive information transmission by interacting with projection neurons and interneurons in the superficial laminae of the SDH. EM2 is a better pain killer than morphine due to its powerful analgesic effect and much weaker side effects (Zadina et al., 1997; Przewlocka et al., 1999; Labuz et al., 2003; Soignier et al., 2004; Fichna et al., 2007; Lazarus, Okada, 2012; Wu et al., 2012). As a highly selective and affinity endogenous agonist for the μ-opioid receptor (MOR), EM2 activates MORs in the SDH via two mechanisms.
Endomorphin-2 (EM2)-immunoreactive (ir) ﬁbers and terminals in the superﬁcial laminae (lamina I and II) of the spinal dorsal horn (SDH) primarily come from neurons in the ipsilateral dorsal root ganglion (DRG), which are important for nociceptive information transmission and modulation. However, the morphological features of EM2-ir neurons and fibers in the DRG and terminals in the SDH under ultrastructural levels have not been completely revealed. The present study observed the distributions of EM2-ir neurons, fibers and terminals in the DRG and SDH and detected their ultrastructural features using immunoelectron microscopy. EM2-ir neurons in the DRG are primarily small or medium in size and account for 17.2% of all neurons in the DRG. EM2-ir large dense-core granule vesicles (LDCVs) are dispersed in the cytoplasm and fibers. Most of the central processes of DRG neurons were thin myelinated and unmyelinated fibers and contained a few EM2-ir LDCVs. An intensive string of EM2-ir fibers with beads and terminals were observed in the superficial laminae of the SDH, other than EM2-ir neurons. EM2-ir products were also detected sparsely in the fibers and terminals. The average diameter of terminals was 94.41 ± 18.13 nm. EM2-ir terminals formed different types of synapses, most of which were asymmetrical (91%). EM2-ir LDCVs colocalized primarily with spherical small clear vesicles in asymmetrical synapses and flat vesicles in symmetrical synapses. The average length of postsynaptic dense zones (PSDs) measured in the asymmetrical synapses was 317.00 ± 31.67 nm. These results indicate that EM2-containing structures are distributed in the cytoplasm of DRG neurons, the central processes and terminals in the SDH and provide morphological evidence for the antinociceptive effects of EM2 in the SDH.
Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance
2016, Neuropharmacology
Citation Excerpt :
Antinocicptive tolerance is one of the major side-effects of opioid analgesics for pain treatment. Our results indicated that repeated administration of EM-2 could induce significant antinociceptive tolerance on day 4, which is consistent with the previous study (Soignier et al., 2004). It is worthy to note that EN-9 had the equivalent analgesic responses over the 6-day course of repeated i.c.v. administration, suggesting no tolerance developed to its central antinociception.
Mounting evidences indicate the functional interactions between neuropeptide FF (NPFF) and opioids, including the endogenous opioids. In the present work, EN-9, a chimeric peptide containing the functional domains of the endogenous opioid endomorphin-2 (EM-2) and NPFF, was synthesized and pharmacologically characterized. In vitro cAMP assay demonstrated that EN-9 was a multifunctional agonist of κ-opioid, NPFF₁ and NPFF₂ receptors. In the mouse tail-flick test, intracerebroventricularly (i.c.v.) administration of EN-9 produced significant antinociception with an ED₅₀ value of 13.44 nmol, which lasted longer than that of EM-2. In addition, EN-9 induced potent antinociception after both intravenous (i.v.) and subcutaneous (s.c.) injection. Furthermore, the experiments using the antagonists of opioid and NPFF receptors indicated that the central antinociception of EN-9 was mainly mediated by κ-opioid receptor, independently on NPFF receptors. Notably, the central antinociception of EN-9 was not reduced over a period of 6 days repeated i.c.v. injection. Repeated i.c.v. administration of EN-9 with the NPFF₁ and NPFF₂ receptors antagonist RF9 resulted in a progressive loss of analgesic potency, consistent with the development of tolerance. Moreover, central administration of EN-9 induced the place conditioning aversion only at a high dose of 60 nmol, but not at low doses. At supraspinal level, only high dose of EN-9 (60 nmol, i.c.v.) inhibited gastrointestinal transit via NPFF receptors. Similarly, systemic administration of EN-9 also inhibited gastrointestinal transit at high doses (10 and 30 mg/kg, i.v.). Taken together, the multifunctional agonist of κ-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects.
Melatonin attenuates the development of antinociceptive tolerance to delta-, but not to mu-opioid receptor agonist in mice
2007, Behavioural Brain Research
The effects of melatonin (Mel) on the development of tolerance to antinociceptive actions induced by mu- and delta-opioid receptor agonists were determined in male Kunming mice. In the mouse tail-flick tests, selective mu and delta receptor agonists were repeatedly administered to mice supraspinally (intracerebroventricularly, i.c.v.) in the absence or presence of melatonin. Administration of endomorphin-1 (EM-1, a mu-opioid receptor agonist) or deltorphin I (del I, a delta-opioid receptor agonist) twice daily for 4 days produced antinociceptive tolerance compared with vehicle controls. Co-administration with melatonin prevented the development of tolerance to deltorphin I analgesia, and this effect was dose dependent. However, melatonin did not affect the development of antinociceptive tolerance to endomorphin-1. Additionally, the attenuation of deltorphin I tolerance by melatonin was reduced by chronic treatment with luzindole (luz), a selective antagonist on the MT₂ receptor subtype. Taken together, these data suggest that melatonin interferes with the neural mechanisms involved in the development of tolerance to delta-opioid agonist analgesia via its receptor.
Development of antinociceptive tolerance and physical dependence following morphine i.c.v. infusion in mice
2005, European Journal of Pharmacology
The chronic i.c.v. infusion of morphine has been reported for rats but not for mice. In the current report, the antinociceptive tolerance to both i.c.v. morphine infusion and s.c. implantation of morphine pellets in mice was compared. Physical dependence after i.c.v. morphine infusion was also evaluated. Osmotic minipumps were filled with morphine (50 mM), connected to i.c.v. cannulae, and implanted s.c. to deliver 50 nmol/h for 3 days (i.e., 3.6 μmol total). Robust jumping precipitated by naloxone (1 mg/kg, s.c.) indicated the development of physical dependence. Tolerance to i.c.v., i.t., and i.v. morphine (6.3-, 2.0-, and 4.4-fold, respectively) was observed using the tail flick test. Mice implanted with pellets containing 75 mg morphine for 3 days (i.e., ∼260 μmol total) were also tolerant to morphine (6.5-, 7.5- and 18-fold, respectively). Thus, the tolerance developed using the two methods was not identical. These results allow comparison of morphine tested by 3 different routes (i.c.v., i.t., and i.v.) after chronic morphine treatment by two routes (i.c.v. and s.c.) in a single study.
Endogenous opiates and behavior: 2004
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This paper is the 27th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over 30 years of research. It summarizes papers published during 2004 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in pain and analgesia; stress and social status; tolerance and dependence; learning and memory; eating and drinking; alcohol and drugs of abuse; sexual activity and hormones, pregnancy, development and endocrinology; mental illness and mood; seizures and neurologic disorders; electrical-related activity and neurophysiology; general activity and locomotion; gastrointestinal, renal and hepatic functions; cardiovascular responses; respiration and thermoregulation; and immunological responses.

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Analgesic tolerance and cross-tolerance to i.c.v. endomorphin-1, endomorphin-2, and morphine in mice

Abstract

Section snippets

Acknowledgements

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Life Sci.

Eur. J. Pharm.

Brain Res.

Neurosci. Lett.

Mol. Brain Res.

Neuroscience

Peptides

Eur. J. Pharm.

Life Sci.

Peptides