Elsevier

Peptides

Volume 21, Issue 7, July 2000, Pages 1071-1080
Peptides

Regular paper
Nociceptin/orphanin FQ and drugs of abuse

https://doi.org/10.1016/S0196-9781(00)00245-XGet rights and content

Abstract

Nociceptin/orphanin FQ (NC) binds with high affinity to the opioid receptor-like1 (ORL1) receptor. NC has been reported to block opioid-induced supraspinal analgesia, and it has been proposed that it may represent a functional antiopioid peptide in the control of brain nociceptive processes. The wide distribution of NC and of its receptors in the central nervous system suggests, however, that it may be involved in the control of a variety of biologic functions. Increasing evidence indicates that it may influence the rewarding and reinforcing properties of drugs of abuse. NC has been shown to abolish the rewarding properties of ethanol and morphine in the place conditioning paradigm, to reduce ethanol consumption in alcohol-preferring rats and to inhibit stress-induced alcohol-seeking behavior. These findings suggest that drugs directed at central NC receptors may represent an interesting approach to the treatment of ethanol and opiate abuse.

Introduction

Nociceptin/orphanin FQ (NC), the endogenous ligand of the opioid receptor-like1 (ORL1) receptor, is a 17-amino acid neuropeptide, structurally related to the opioid peptide dynorphin A [60], [74], [88], [89]. Despite its structural homology with opioid peptides, NC does not bind to μ, δ, and κ opioid receptors, nor do opioid peptides activate the ORL1 receptor [87]. Activation of membrane ORL1 receptors by NC results in the same sequence of intracellular events induced by opioid receptors, namely negative coupling with adenylyl cyclase, activation of inwardly rectifying K+ channels, and inhibition of Ca2+ current in a pertussis toxin-sensitive manner [18], [32], [59], [60], [89]. However, these cellular responses to NC are insensitive to naloxone [18], [32], confirming that the pharmacological actions of this peptide are not mediated by the classic opioid receptors. Detailed structure analysis revealed important differences between ORL1 and μ, δ, and κ opioid receptors [74], [87], [88], suggesting that separate mutations might have led to a coordinated pharmacological separation of the NC system from the opioid system [58], [88]. This view is supported by brain mapping studies showing that the neuroanatomical distribution of NC and its receptor differs from that of opioid peptides and opioid receptors [4], [18], [25], [36], [70], [98].

NC has been reported to block opioid-induced supraspinal analgesia, and it has been proposed that it may act as a functional antiopioid peptide in the control of brain nociceptive processes [63], [65], [73].

It is well known that the endogenous opioid system also plays a major role in mediating the rewarding and reinforcing actions of opiates and other abused drugs [33], [34], [102], [103]. Thus, several studies have recently evaluated whether NC behaves as a functional antiopioid peptide in relation to the motivational properties of opiates and ethanol as well. The aim of the present article is to review these studies and to discuss new directions for future research about the effects of NC on drug abuse.

Section snippets

The brain reward system

More than 40 years ago, Olds and Milner discovered that direct electrical stimulation of different brain areas can be rewarding and act as a reinforcer [75]. Afterwards, a large number of studies using electrophysiological techniques, microdialysis, electrical self-stimulation and drug self-administration, have been conducted to identify the neuroanatomical and neurochemical pathways of the “brain reward system” [46], [113].

The medial forebrain bundle, connecting the olfactory tubercle (OT),

Nociceptin/orphanin FQ and ethanol intake in alcohol-preferring rats

A study of our group has shown that ICV treatment with a dose as low as 500 ng/rat of NC significantly modifies ethanol consumption in genetically selected Marchigian Sardinian (msP) alcohol-preferring rats [16]. In a 7-day subchronic treatment, NC attenuated alcohol drinking in freely feeding and drinking msP rats, which were offered 10% ethanol 30 min/day, at the beginning of the dark phase of the light cycle. The intake of 10% ethanol became significantly lower than that of controls after 3

Nociceptin/orphanin FQ and the rewarding properties of morphine

NC was first indicated as an antiopioid peptide for its property to reverse morphine-induced analgesia [63], [64]. However, a recent study by Murphy et al. [66], as well as work simultaneously carried out in our laboratory [3] suggests that the antiopioid action of NC also extends to the motivational properties of morphine.

Murphy and co-workers reported that ICV administration of NC at doses of 5000–20000 ng/rat blocked CPP induced by subcutaneous (s.c.) injections of 3 mg/kg of morphine.

In our

Nociceptin/orphanin FQ and psychostimulants

At present, no study has been published on the effect of NC on the rewarding effects of psychostimulants.

It has been reported that NC does not alter locomotor sensitization induced by cocaine [69]. This finding, together with the observation that NC fails to inhibit locomotor sensitization induced by morphine, supports the idea that NC does not interfere with the process of sensitization to drugs of abuse.

Nociceptin/orphanin FQ versus opioid antagonists

Opioid receptor antagonists represent important pharmacological tools to treat abstinent individuals with a history of opiate abuse and dependence. The long acting drug, naltrexone, has been approved by the Food and Drug Administration for the treatment of alcohol dependence. However, a relevant clinical problem with opioid receptor antagonists is low compliance, probably related to the aversive properties of these drugs [47], [86], [108]. In laboratory animals, place and taste aversion have

Conclusions

NC was isolated only a few years ago, and promptly attracted the attention of many researchers, mainly for its effects on nociceptive processes. However, increasing evidence suggests that this peptide may also play a crucial role in the regulation of reward mechanisms and drug abuse processes.

The data discussed in this review indicate that NC behaves as a functional antiopioid peptide in regard to the motivational properties of opiates and ethanol. Indeed, low ICV doses of NC (500–1000 ng/rat)

Acknowledgements

This study was supported by grant from the University of Camerino and MURST (Cofin99). The authors thank Sheila Beatty for linguistic revision of this article.

References (115)

  • G.L. Gessa et al.

    Low doses of ethanol activate dopaminergic neurons in the ventral tegmental area

    Brain Res

    (1985)
  • H.J. Groenewegen et al.

    Organization of the output of the ventral striatopallidal system in the ratventral pallidal efferents

    Neuroscience

    (1993)
  • L. Heimer et al.

    Specificity of projection patterns of accumbal core and shell in the rat

    Neuroscience

    (1991)
  • S.C. Heinrichs et al.

    Endogenous corticotropin-releasing factor modulates feeding induced by neuropeptide Y or a tail-pinch stressor

    Peptides

    (1992)
  • S.C. Heinrichs et al.

    Corticotropin-releasing factor in the paraventricular nucleus modulates feeding induced by neuropeptide Y

    Brain Res

    (1993)
  • G. Henderson et al.

    The orphan opioid receptor and its endogenous ligand nociceptin/orphanin FQ

    Trends Pharmacol Sci

    (1997)
  • P. Hyytiä et al.

    GABAA receptor antagonism in the extended amygdala decreases ethanol self-administration in rats

    Eur J Pharmacol

    (1995)
  • T.C. Kirkham et al.

    Differential effects of CGS 8216 and naltrexone on ingestional behaviour

    Pharmacol Biochem Behav

    (1987)
  • G.F. Koob

    Drugs of abuseAnatomy, pharmacology and function of reward pathways

    Trends Pharmacol Sci

    (1992)
  • G.F. Koob et al.

    Neuroscience of addiction

    Neuron

    (1998)
  • M.J. Kreek et al.

    Drug dependencestress and disregulation of brain reward pathways

    Drug Alcohol Depend

    (1998)
  • S. Lapalu et al.

    Comparison of the structure-activity relationships of nociceptin and dynorphin A using chimeric peptides

    FEBS Lett

    (1997)
  • A.D. Le et al.

    Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress

    Neuropsychopharmacology

    (1999)
  • W.J. McBride et al.

    Localization of brain reinforcement mechanismsintracranial (i

    c.) self-administration and i.c. place-conditioning studies. Behav Brain Res

    (1999)
  • F. Meng et al.

    Moving from the orphanin FQ receptor to an opioid receptor using four point mutations

    J Biol Chem

    (1996)
  • J.C. Meunier

    Nociceptin/orphanin FQ, and the opioid receptor-like ORL1 receptor

    Eur J Pharmacol

    (1997)
  • M.J. Millan et al.

    Long-term blockade of μ-opioid receptors suggests a role in control of ingestive behaviour, body weight and core temperature in the rat

    Brain Res

    (1988)
  • J.S. Mogil et al.

    Orphanin FQ is a functional anti-opioid peptide

    Neuroscience

    (1996)
  • J.S. Mogil et al.

    Functional antagonism of μ-, δ- and κ-opioid antinociception by orphanin FQ

    Neurosci Lett

    (1996)
  • N.P. Murphy et al.

    Orphanin FQ/nociceptin blocks acquisition of morphine place preference

    Brain Res

    (1999)
  • N.P. Murphy et al.

    Intracerebroventricular orphanin FQ/nociceptin suppresses dopamine release in the nucleus accumbens of anaesthetized rats

    Neuroscience

    (1996)
  • S. Narayanan et al.

    Orphanin FQ and behavioral sensitization to cocaine

    Pharmacol Biochem Behav

    (1999)
  • S. Nikolaus et al.

    Reinforcing effects of neurokinin substance P in the ventral pallidummediation by the tachykinin NK1 receptor

    Eur J Pharmacol

    (1999)
  • Y. Noda et al.

    Loss of antinociception induced by naloxone benzoylhydrazone in nociceptin receptor-knockout mice

    J Biol Chem

    (1998)
  • G. Panagis et al.

    Ventral pallidum self-stimulation induces stimulus dependent increase in c-fos expression in reward-related brain regions

    Neuroscience

    (1997)
  • L.A. Parker et al.

    Naltrexone-induced aversionsassessment by place conditioning, taste reactivity, and taste avoidance paradigms

    Pharmacol Biochem Behav

    (1992)
  • H.O. Pettit et al.

    Dopamine in the nucleus accumbens during cocaine self-administration as studied by in vivo microdialysis

    Pharmacol Biochem Behav

    (1989)
  • J. Rabinowitz et al.

    Compliance to naltrexone treatment after ultra-rapid opiate detoxificationan open label naturalistic study

    Drug Alcohol Depend

    (1997)
  • R.K. Reinscheid et al.

    Structure-activity relationship studies on the novel neuropeptide orphanin FQ

    J Biol Chem

    (1996)
  • R.K. Reinscheid et al.

    Structures that delineate orphanin FQ and dynorphin A pharmacological selectivities

    J Biol Chem

    (1998)
  • D. Roberts et al.

    Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens

    Pharmacol Biochem Behav

    (1980)
  • T.E. Robinson et al.

    The neural basis of drug cravingan incentive-sensitization theory of addiction

    Brain Res Rev

    (1993)
  • G.C. Rossi et al.

    Novel receptor mechanisms for heroin and morphine-6 β-glucuronide analgesia

    Neurosci Lett

    (1996)
  • H.H. Samson et al.

    Neurobiology of alcohol abuse

    Trends Pharmacol Sci

    (1992)
  • E. Acquas et al.

    Blockade of acquisition of drug-conditioned place aversion by 5HT3 antagonists

    Psychopharmacology

    (1990)
  • S. Angeletti et al.

    Effect of nociceptin (NC) on morphine-induced conditioned place preference (CPP) in rats

    Regul Pept

    (1999)
  • B. Anton et al.

    Immunohistochemical localization of ORL-1 in the central nervous system of the rat

    J Comp Neurol

    (1996)
  • M. Barrot et al.

    Functional heterogeneity in dopamine release and in the expression of fos-like proteins within the rat striatal complex

    Eur J Neurosci

    (1999)
  • A.Y. Bespalov et al.

    Effects of test conditions on the outcome of place conditioning with morphine and naltrexone in mice

    Psychopharmacology

    (1999)
  • S.B. Caine et al.

    Effects of D-1 and D-2 antagonists on cocaine self-administration under different schedules of reinforcement in the rat

    J Pharmacol Exp Ther

    (1994)
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