Role of nociceptin in the modulation of nociception in the arcuate nucleus of rats

doi:10.1016/j.brainres.2004.07.073

Brain Research

Volume 1025, Issues 1–2, 29 October 2004, Pages 67-74

https://doi.org/10.1016/j.brainres.2004.07.073 Get rights and content

Abstract

Neuropeptide nociceptin/orphanin FQ is the endogenous ligand for the opioid-receptor-like receptor 1 (ORL1), mediating essential functions in the central and peripheral nervous systems. The present study was performed to investigate the role of nociceptin and ORL1 receptor in nociception and morphine-induced antinociception in the arcuate nucleus of hypothalamus in rats. Hindpaw withdrawal latencies (HWL) were measured by hot-plate and Randall Selitto tests. The HWL to both thermal and mechanical stimulation decreased significantly after intra-arcuate nucleus injection of nociceptin in a dose-dependent manner. The effect of nociceptin was blocked significantly by subsequent intra-arcuate nucleus administration of [Nphe¹]nociceptin(1–13)-NH₂, an ORL1 receptor antagonist. Furthermore, an intra-arcuate nucleus injection of nociceptin dramatically attenuated the antinociceptive effect induced by morphine either injected in the same site or applied intraperitoneally. These results suggest that nociceptin in the arcuate nucleus induces a hyperalgesic effect by acting on ORL1 receptors. The present study also demonstrates an interaction between nociceptin and opioids in the arcuate nucleus of the hypothalamus.

Introduction

Discovery of the opioid-receptor-like (ORL1) receptor and its endogenous ligand nociceptin/orphanin FQ has led to a new understanding of the endogenous pain modulation system [17], [24]. Nociceptin is a widely distributed neuropeptide which contains 17 amino acids. ORL1 receptor and nociceptin possess significant similarities with opioid receptors and opioid peptides respectively in their molecular sequences as well as in their involvement of signal transduction pathways [15], [36], but their physiological functions and pharmacological effects are quite different [16]. Although nociceptin acting on the ORL1 receptor activates the same inhibitory G-protein-mediated signal transduction mechanisms as opioids, its effects are quite different from those of opioids in the periphery, spinal cord and supraspinal regions, with both pro- and anti-nociceptive activity described (for a review, see Ref. [18]).

Initial work with intracerebroventricular administration of nociceptin demonstrated a hyperalgesic, anti-opioid effect [17], [8]. Specific brain regions where ORL1 receptors are expressed have been identified with autoradiography, in situ hybridization and immunocytochemistry, which include structures known to be involved in pain modulation, such as the periaqueductal gray (PAG), locus coeruleus (LC), rostral ventral medulla (RVM) and the amygdala [13]. Subsequent studies of microinjection of nociceptin accompanied by low intensity nociceptive testing have continued to elucidate its role. In the amygdala, nociceptin produces a dose-dependent analgesic effect [26]. In the PAG, microinjection of nociceptin produced facilitation of C-fiber-evoked response at the wide dynamic range neurons in the spinal cord, reflecting a reduction in descending inhibitory input from the PAG and thus a pro-nociceptive effect [34]. In the RVM, microinjection of nociceptin reverses opioid-induced analgesia [11], [21]. In the LC and ventral tegmental area, chronic application of morphine produces upregulation of tyrosine hydroxylase, which may mediate some of its supraspinal effects. Nociceptin has been shown to inhibit the effect of morphine on the upregulation of tyrosine hydroxylase [28].

The arcuate nucleus of the hypothalamus has not previously been specifically investigated with microinjection of nociceptin. Dense expression of ORL1 receptor has been observed in the arcuate nucleus [6], [19]. Endogenous opioid peptides and their receptors are also abundantly expressed in the same area [23]. The arcuate nucleus has been recognized as an essential site in the endogenous pain-modulation system [1], [14], [32]. The present study was to investigate the role of nociceptin in the modulation of nociception and the possible interaction between nociceptin-ORL1 system and opioid system in the arcuate nucleus of the rat.

Section snippets

Animals

Experiments were performed on male Sprague–Dawley rats weighing 200–250 g (Experimental Animal Center of Peking University, Beijing, China). Animals were individually housed in cages maintained in a room temperature of 24±2 °C with a normal day/night cycle, with free access to water and food. All experiments using laboratory animals were conducted according to the guidelines of the International Association for the Study of Pain [37], and were approved by Peking University and the Institutional

Effects of intra-arcuate nucleus administration of nociceptin on hindpaw withdrawal responses to thermal and mechanical stimulation

Rats were tested at 5, 15, 30 and 60 min after receiving an intra-arcuate nucleus injection of 0.5 nmol (n=6), 1 nmol (n=8) or 4 nmol (n=7) of nociceptin, or 1 μl of 0.9% saline (n=6) as the control. The results are shown in Fig. 2.

The HWLs to thermal and mechanical stimulation decreased significantly after intra-arcuate nucleus injection of 1 and 4 nmol of nociceptin, as compared with the control. In the 0.5-nmol nociceptin group, there was no significant change in HWL as compared with the

Discussion

The results of this study show that intra-arcuate nucleus administration of 4 nmol of nociceptin produced a hyperalgesic effect in rats, which was antagonized significantly by subsequent intra-arcuate nucleus injection of 2 or 4 nmol of the ORL1 receptor antagonist [Nphe¹]nociceptin(1–13)-NH₂. In vitro data show that nociceptin and the antagonist [Nphe¹]nociceptin(1–13)-NH₂ have very different affinities to ORL1 receptor [3]. Our results indicated that in vivo they were able to compete with

Conclusion

The present study shows that intra-arcuate nucleus administration of nociceptin decreases the HWL in rats and this effect is antagonized by subsequent injection of [Nphe¹]nociceptin(1–13)-NH₂ in a dose-dependent manner, indicating that in the arcuate nucleus nociceptin produces hyperalgesia which is mediated by the ORL1 receptor. Furthermore, the antinociceptive effect induced by intra-arcuate nucleus administration of morphine is attenuated significantly by nociceptin, indicating a possible

Acknowledgements

The study was supported by funds from the National Natural Science Foundation of China (Dr. Long-Chuan Yu), and the NIH grants AR45570 and NS042593 (Dr. Pierce Palmer).

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The nociceptin/orphanin FQ-like opioid peptide in nervous periesophageal ganglia of land snail Helix aspersa
2013, Brain Research
Citation Excerpt :
Moreover, in a previous communication we reported the thermonociceptive effect of N/OFQ and the analgesic effect of its antagonist, the pseudopeptide [Phe1Psi(CH2NH)Gly2]-nociceptin(1-13)-NH2 in H. aspersa (Miller.-Pérez et al., 2008). We observed that N/OFQ can act as an antiopiod system, crucial for the modulation of thermonociception in the snail, as has been previously reported in mammals (Mogil et al., 1996; Grisel et al., 1998; Li et al., 2004; Chen et al., 2007 among others). We found that the antibody to N/OFQ recognizes N/OFQ-like material in H. aspersa nervous tissue.
The neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor are members of the endogenous opioid peptide family. In mammals N/OFQ modulates a variety of biological functions such as nociception, food intake, endocrine, control of neurotransmitter release, among others. In the molluscs Cepea nemoralis and Helix aspersa the administration of N/OFQ produces a thermopronociceptive effect. However, little is known about its existence and anatomic distribution in invertebrates. The aim of this study was to provide a detailed anatomical distribution of N/OFQ like peptide immunoreactivity (N/OFQ-IL), to quantify the tissue content of this peptide, as well as to demostrate molecular evidence of N/OFQ mRNA in the nervous tissue of periesophageal ganglia of the land snail H. aspersa. Immunohistochemical, immunocytochemical, radioimmunoanalysis (RIA) and reverse transcription-polymerase chain reaction (RT-PCR) techniques were used. With regard to RT-PCR, the primers to detect expression of mRNA transcripts from H. aspersa were derived from the rat N/OFQ opioid peptide. We show a wide distribution of N/OFQ-IL in neurons and fibers in all perioesophageal ganglia, fibers of the neuropile, nerves, periganglionar connective tissue, aortic wall and neurohemal sinuses. The total amount of N/OFQ-IL in the perioesophageal ganglia (7.75±1.75 pmol/g of tissue) quantified by RIA was similar to that found in mouse hypothalamus (10.1±1.6 pmol/g of tissue). In this study, we present molecular evidence of N/OFQ mRNA expression. Some N/OFQ-IL neurons have been identified as neuroendocrine or involved in olfaction, hydro-electrolyte regulation, feeding, and thermonociception. Therefore, we suggest that N/OFQ may participate in these snail functions.
Involvement of ORL1 receptor and ERK kinase in the orphanin FQ-induced nociception in the nucleus accumbens of rats
2008, Regulatory Peptides
Nociceptin/orphanin FQ (N/OFQ) is a heptadecapeptide, which has been identified as an endogenous ligand of the opioid receptor-like (ORL1) receptor. The present study investigated the nociceptive effect of intra-nucleus accumbens (intra-NAc) injection of OFQ, and the involvement of ERK pathway in such effect. Intra-NAc injection of OFQ (0.1, 0.5, 1 nmol) dose-dependently decreased the nociceptive thresholds on the hindpaw withdrawal response to thermal and mechanical stimulation in rats. Moreover, the intra-NAc injection of OFQ-induced decreases in HWLs were antagonized by intra-NAc injection of (Nphe¹)nociceptin(1–13)NH₂, an antagonist of ORL1 receptor, in a dose-dependent way. Furthermore, the OFQ-induced nociception could be attenuated by pretreatment with the mitogen-activated protein kinase/ERK kinase (MEK) inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(2-aminopheylthio)butadiene (U0126). Our results demonstrate that OFQ induces nociceptive effects in NAc. The effect was blocked by the antagonist (Nphe¹)nociceptin(1–13)NH₂ and attenuated by U0126, suggesting that the activation of ERK pathways is involved in the OFQ-induced nociceptive effect in the NAc of rats.
Involvement of CGRP and CGRPl receptor in nociception in the basolateral nucleus of amygdala of rats
2008, Neuroscience Letters
The present study was performed to investigate the role of calcitonin gene-related peptide (CGRP) and its receptor in nociception in the basolateral nucleus of amygdala (BLA) of rats. Hindpaw withdrawal latencies (HWLs) to noxious thermal and mechanical stimulations were measured by hot plate and Randall Selitto tests. The HWL to both thermal and mechanical stimulations increased significantly after intra-BLA administration of 1.0 or 2.0 nmol CGRP, but not 0.5 nmol, indicating that CGRP plays an anti-nociceptive role in BLA of rats. The anti-nociceptive effect of 1.0 nmol CGRP was blocked significantly by administration of 1.0 or 2.0 nmol CGRP8-37, a selective antagonist of CGRP1 receptor, which suggests that the anti-nociceptive effect of CGRP is mediated by the CGRP1 receptor. Taken together, the results indicate that both CGRP and CGRP1 receptor play important roles in nociceptive modulation in the BLA of rats.
Role of nociceptin/orphanin FQ and the pseudopeptide [Phe<sup>1</sup>Ψ(CH<inf>2</inf>NH)Gly<sup>2</sup>]-nociceptin(1-13) -NH<inf>2</inf> and their interaction with classic opioids in the modulation of thermonociception in the land snail Helix aspersa
2008, European Journal of Pharmacology
The role in nociception of nociceptin/orphanin FQ (N/OFQ) and its receptor, the opioid receptor-like 1 (NOP), remains unclear because this peptide has been implicated in both suppression and enhancement of nociception. The present work characterises the effects of N/OFQ and the NOP receptor antagonist, the pseudopeptide [Phe¹Ψ(CH₂NH)Gly²]-nociceptin(1–13)-NH₂ (Phe¹Ψ), on thermonociception in the snail Helix aspersa using the hot plate assay. Additionally, the possible interaction of each of these compounds with morphine or dynorphin A_1–17 and naloxone was studied. Compounds were administered into the hemocoel cavity of H. aspersa and the latency to the aversive withdrawal behaviour recorded. Dose–response and time course curves were done. N/OFQ and naloxone produced a similar dose-dependent pronociceptive effect; however, N/OFQ reached its peak effect earlier and was 30 times more potent than naloxone. [Phe¹Ψ(CH₂NH)Gly²]-nociceptin(1–13)-NH₂ and the opioid agonists, morphine and dynorphin A_1–17 produced antinociception with a similar efficacy, but [Phe¹Ψ(CH₂NH)Gly²]-nociceptin(1–13)-NH₂ reached its peak effect more rapidly and lasted longer than that of dynorphin A_1–17 and morphine. [Phe¹Ψ(CH₂NH)Gly²]-nociceptin(1–13)-NH₂ was 50 times less potent than dynorphin A_1–17, but 30 times more potent than morphine. N/OFQ significantly reduced morphine and dynorphin A_1–17-induced antinociception. Combined administration of low doses of [Phe¹Ψ(CH₂NH)Gly²]-nociceptin(1–13)-NH₂ and morphine or dynorphin A_1–17 produced a potent antinociceptive effect. Sub-effective doses of naloxone and N/OFQ also synergised to produce pronociception. Data suggest that these two opioid classes regulate nociception through parallel systems. The H. aspersa model appears as a valuable experimental preparation to continue the study of these opioid receptor systems.
Nociceptin/orphanin FQ decreases serotonin efflux in the rat brain but in contrast to a κ-opioid has no antagonistic effect on μ-opioid-induced increases in serotonin efflux
2007, Neuroscience
Similar to κ-opioids, nociceptin/orphanin FQ (OFQ) exerts anti-μ-opioid actions. This may involve interactions within the circuitry controlling 5-HT neurons in the dorsal raphe nucleus (DRN) that project to the nucleus accumbens (NAcc). To test this hypothesis, we compared the effects of OFQ and κ-opioids on 5-HT efflux in the CNS of freely behaving rats. First, OFQ (30–300 μM) infused into the DRN for 120 min dose-dependently decreased 5-HT efflux in the DRN. The opioid receptor-like 1 (ORL-1) antagonist [Nphe¹]nociceptin(1–13)NH₂ blocked this effect. Using dual-probe microdialysis we observed that OFQ (300 μM) infused into the DRN for 120 min produced parallel decreases in 5-HT efflux in the DRN and NAcc, suggesting that ORL-1 receptors in the DRN inhibit serotonergic neurons projecting to the NAcc. Also, 5-HT efflux in the NAcc was dose-dependently decreased during OFQ (30–300 μM) infusion into the NAcc. This suggests that OFQ can reduce 5-HT efflux in the NAcc both by inhibiting serotonergic neurons in the DRN and by stimulating ORL-1 receptors in the NAcc. Similar to OFQ, the κ-opioids U-50,488 (300 μM) and dynorphin A(1–13) (300 μM) infused into the DRN for 120 min decreased 5-HT efflux in the DRN. This effect was blocked only by the κ-opioid receptor antagonist nor-BNI. Lastly, we compared the ability of OFQ and U-50,488 to block μ-opioid-induced increases in 5-HT. The κ-opioid U-50,488 (1000 μM) attenuated the increase in 5-HT induced by the μ-opioid agonist endomorphin-1 (300 μM) in the DRN. In contrast, OFQ (300–1000 μM) did not alter μ-opioid-induced increases in 5-HT efflux. In summary, κ-opioids and OFQ both decreased 5-HT efflux in the CNS. However, in contrast to κ-opioids, which reversed μ-opioid-induced increases in 5-HT efflux, the anti-μ-opioid effects of OFQ apparently do not involve changes in 5-HT transmission under our experimental conditions.
Endogenous opiates and behavior: 2004
2005, Peptides
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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¹: Present address: Laboratory of Applied Pharmacology, Weifang Medical College, Weifang, Shandong 261042, China.

²: Present address: Department of Anaesthesia, St Vincent's Hospital, Melbourne, Australia..

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Research reportRole of nociceptin in the modulation of nociception in the arcuate nucleus of rats

Abstract

Introduction

Section snippets

Animals

Effects of intra-arcuate nucleus administration of nociceptin on hindpaw withdrawal responses to thermal and mechanical stimulation

Discussion

Conclusion

Acknowledgements

FEBS Lett.

Trends Neurosci.

Peptides

Neurosci. Lett.

Neurosci. Lett.

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol.

Neuron

Brain Res.

Brain Res.

Brain Res. Mol. Brain Res.

Neuroscience

Brain Res.

Brain Res.

Neuroscience

Pain

Beta-endorphin: cellular localization, electrophysiological and behavioral effects

Adv. Biochem. Psychopharmacol.

Characterization of [Nphe(1)]nociceptin(1–13)NH(2), a new selective nociceptin receptor antagonist

Br. J. Pharmacol.

Research report
Role of nociceptin in the modulation of nociception in the arcuate nucleus of rats