Elsevier

Peptides

Volume 21, Issue 7, July 2000, Pages 1051-1062
Peptides

Regular paper
The hyperphagic effect of nociceptin/orphanin FQ in rats.

https://doi.org/10.1016/S0196-9781(00)00243-6Get rights and content

Abstract

Nociceptin/orphanin FQ (NC), the endogenous ligand of the opioid receptor-like1 (ORL1) receptor, has been reported to stimulate feeding in rats. The present article reviews the studies so far published on the effect of NC on food intake and reports new findings concerning the sensitivity of brain regions to the hyperphagic effect of NC in rats. The results obtained indicate that the hypothalamic arcuate nucleus is the most sensitive site among the brain regions so far investigated. On the basis of these findings and of the neurochemical and electrophysiological effects of NC, possible mechanisms of action and possible interactions with other neurotransmitter systems affecting feeding are discussed.

Introduction

Nociceptin/orphanin FQ (NC) shows structural homology with opioid peptides, particularly with dynorphin A [62], [84]. Moreover, the opioid receptor-like1 (ORL1) receptor [10], [19], [29], [64], for which NC is considered to be the endogenous ligand, exhibits marked structural analogy with opioid receptors, particularly with the κ receptor. Indeed, NC lacks the N-terminal tyrosine necessary for activation of opioid receptors [53], [83], [84]; however, the NC receptor acts through the same intracellular mechanisms as classic opioid receptors, namely inhibition of adenylyl cyclase, activation of K+ channels, and/or inhibition of Ca2+ channels [61].

Endogenous opioid peptides are known to influence feeding behavior. Dynorphin A, the endogenous ligand of the κ opioid receptor, dynorphin [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], and other κ opioid receptor agonists induce feeding in rats [22], [65], [66]. Agonists at μ opioid receptors increase food intake in freely feeding rats, while μ opioid receptor antagonists reduce it [30], [32]. Antisense oligodeoxynucleotides directed against each of the four exons of the MOR-1 clone reduce spontaneous feeding and body weight in rats [55].

These observations, together with the localization of NC and of ORL1 receptors in regions of the central nervous system involved in feeding control [3], [10], [19], [24], [29], [38], [64], have led to interest in the possible effects of NC on food intake. Shortly after the discovery of NC, Pomonis et al. [82] reported that injections of NC (1–10 nmol/rat) into the lateral cerebroventricle (LV) increase food intake in freely feeding and drinking rats. Stratford et al. [97] showed that microinjections of NC into the ventromedial hypothalamus (VMH) or the shell of the nucleus accumbens (NAC) markedly increase food intake.

The aim of the present article is to review the few studies published to date on the hyperphagic effect of NC, to report new findings on the sensitivity of brain regions to this effect of NC, and to speculate about the peptide’s possible mechanisms of action. Lastly, directions for further research on the hyperphagic action of NC and on its role in feeding control will be discussed.

Section snippets

The hyperphagic effect

Since the first report of Pomonis et al. [82], other groups have consistently observed that injections of NC into the LV evoke feeding in rats. At present, the rat is the only animal species that has been tested.

Site of action

Stratford et al. [97] reported a marked increase in food intake following microinjections of NC (2.5–25 nmol/rat) into either the VMH or the shell of the NAC, the VMH being more sensitive than the NAC. However, these doses are in the range of those active following injection in the LV; therefore, the VMH and the shell of the NAC may not represent primary sites of action for the hyperphagic effect of NC. Recent experiments of our group have evaluated the sensitivity of additional brain sites to

Opioids

Pomonis et al. [82] have reported that subcutaneous (s.c.) pretreatment with naloxone, 1 mg/kg, abolishes the hyperphagic effect of NC. Leventhal et al. [54] reported that naltrexone pretreatment (10 μg/rat in the LV) reduces NC-induced hyperphagia. These findings raise the question of the possible involvement of opioid mechanisms in the mediation of the hyperphagic effect of NC.

Indeed, NC shows high structural homology with opioid peptides, particularly with dynorphin A [62], [83]. However, NC

Pharmacological characterization of the receptor

The pharmacological characterization of the receptor that mediates the hyperphagic effect of NC has been carried out by our group using several NC-related peptides, previously characterized in in vitro preparations as NC receptor full agonists, NC and NC(1–13)NH2, partial agonist or antagonist, [F/G)]NC(1–13)NH2, antagonist, [Nphe1]NC(1–13)NH2, or as inactive compounds, NC(1–12)NH2 and NC(1–9)NH2 [7], [12], [13], [14], [35], [36].

Feeding control

The information so far available on the possible role of NC in feeding control in physiological or pathologic conditions is definitely insufficient to draw any conclusion. The following reports (mostly presented in the form of abstract), however, provide interesting suggestions for further studies.

Major changes in food intake in knockdown rats for the NC receptor have not been reported [77], suggesting that NC may not exert an important role in feeding control under basal conditions. Antisense

Nociceptin and the circadian rhythm

Neurons of the suprachiasmatic nucleus represent the principal circadian pacemaker of mammals. These neurons have been reported to respond in a dose-dependent manner to NC with an outward current and a reduction in the NMDA receptor-mediated increase in intracellular Ca2+ [2].

Feeding behavior is strongly related to the circadian rhythm. Thus, the response to orexigenic agents can be strongly influenced by the phase of the light/dark cycle in which they are administered [37]. On the other hand,

Conclusions

After the first report of the hyperphagic effect of NC [82], only a few studies have further investigated the effect. Attention has been focused on possible sites of action for the effect (ref. 97 and the present study) and on the pharmacological characterization of the NC receptor mediating hyperphagia [78].

Probably, the most interesting result of the studies concerning the pharmacological characterization of the NC receptor mediating hyperphagia is the identification of a selective antagonist

Acknowledgements

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

References (108)

  • L. Grandison et al.

    Stimulation of food intake by muscimol and beta endorphin

    Neuropharmacology

    (1977)
  • J.E. Grisel et al.

    [Phe1psi(CH2-NH)Gly2]-nociceptin-(1–13)NH2 acts as an agonist of the orphanin FQ/nociceptin receptor in vivo

    Eur J Pharmacol

    (1998)
  • T. Houtani et al.

    Structure and regional distribution of nociceptin/orphanin FQ precursor

    Biochem Biophys Res Commun

    (1996)
  • D. Huszar et al.

    Targeted disruption of the melanocortin-4-receptor results in obesity in mice

    Cell

    (1997)
  • A. Inui

    Feeding and body weight regulation by hypothalamic neuropeptides—mediation of the actions of leptin

    Trends Neurosci

    (1999)
  • H.C. Jackson et al.

    Endogenous opioids may be involved in idazoxan-induced food intake

    Neuropharmacology

    (1992)
  • A. Kask et al.

    Selective antagonist for the melanocortin-4 receptor (HS014) increases food intake in free-feeding rats

    Biochem Biophys Res Commun

    (1998)
  • H. Khachaturian et al.

    Anatomy of the CNS opioid systems

    Trends Neurosci

    (1985)
  • J.Z. Kiss et al.

    Analysis of the ACTH/β-End/α-MSH-immunoreactive afferent input to the hypothalamic paraventricular nucleus of the rat

    Brain Res

    (1984)
  • J.E. Koch et al.

    Alterations in deprivation, glucoprivic and sucrose intake following general, mu and kappa opioid antagonists in the hypothalamic paraventricular nucleus of rats

    Neuroscience

    (1995)
  • S. Lapalu et al.

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

    FEBS Lett

    (1997)
  • L. Leventhal et al.

    Orphan opioid receptor antisense probes block orphanin FQ-induced hyperphagia

    Eur J Pharmacol

    (1998)
  • A.S. Levine et al.

    Neuropeptide Ya potent inducer of consummatory behavior in rats

    Peptides

    (1984)
  • J.C. Meunier

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

    Eur J Pharmacol

    (1997)
  • C. Mollereau et al.

    ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization

    FEBS Lett

    (1994)
  • J.E. Morley et al.

    Dynorphin-(1–13) induces spontaneous feeding in rats

    Life Sci

    (1981)
  • R. Poggioli et al.

    ACTH-(1–24) and α-MSH antagonize feeding behavior stimulated by kappa opiate agonists

    Peptides

    (1986)
  • C. Polidori et al.

    Neuropeptide Y receptor(s) mediating feeding in the ratcharacterization with antagonists

    Peptides

    (2000)
  • R.K. Reinscheid et al.

    Structures that delineate orphanin FQ and dynorphin-A pharmacological selectivities

    J Biol Chem

    (1998)
  • E.H. South et al.

    Over-consumption of preferred foods following capsaicin pretreatment of the area postrema and adjacent nucleus of the solitary tract

    Brain Res

    (1983)
  • J.M. Stapleton et al.

    Naloxone inhibits diazepam-induced feeding in rats

    Life Sci

    (1979)
  • T.R. Stratford et al.

    Blockade of GABAA receptors in the medial ventral pallidum elicits feeding in satiated rats

    Brain Res

    (1999)
  • T.R. Stratford et al.

    Specific changes in food intake elicited by blockade or activation of glutamate receptors in the nucleus accumbens shell

    Behav Brain Res

    (1998)
  • Y.S. Allen et al.

    Neuropeptide Y distribution in the rat brain

    Science

    (1983)
  • C.N. Allen et al.

    Orphanin-FQ/nociceptin (OFQ/N) modulates the activity of suprachiasmatic nucleus neurons

    J Neurosci

    (1999)
  • B. Anton et al.

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

    J Comp Neurol

    (1996)
  • D.G. Baskin et al.

    Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus

    Diabetes

    (1999)
  • D.G. Baskin et al.

    Leptin sensitive neurons in the hypothalamus

    Horm Metab Res

    (1999)
  • A.M. Basso et al.

    Feeding induced by GABAA receptor stimulation within the nucleus accumbens shellregional mapping and characterization of macronutrient and taste preference

    Behav Neurosci

    (1999)
  • R. Bigoni et al.

    Characterization of nociceptin receptors in the peripheryin vitro and in vivo studies

    Naunyn-Schmiedeberg’s Arch Pharmacol

    (1999)
  • Calo’ G, Guerrini R, Bigoni R, et al. Characterization of [Nphe1]NC(1–13)NH2, a novel selective nociceptin receptor;...
  • G. Calo’ et al.

    Pharmacological characterization of nociceptin receptoran in vitro study

    Can J Physiol Pharmacol

    (1997)
  • G. Calo’ et al.

    Pharmacological characterization of the nociceptin receptor mediating hyperalgesia in the mouse tail withdrawal assay

    Br J Pharmacol

    (1998)
  • S. Candeletti et al.

    Prolonged effects of centrally administered nociceptin in the rat

    Regul Pept

    (1999)
  • Candeletti S, Guerrini R, Calo’ G, Ferri S. Effects of the nociceptin receptor antagonist...
  • K.J. Carpenter et al.

    Evidence that [Phe1psi(CH2-NH)Gly2]-nociceptin-(1–13)NH2, a peripheral ORL-1 receptor antagonist, acts as an agonist in the rat spinal cord

    Br J Pharmacol

    (1998)
  • A. Catania et al.

    α-Melanocyte stimulating hormone in the modulation of host reactions

    Endocr Rev

    (1993)
  • R.J. Contreras et al.

    Area postremapart of the autonomic circuitry of caloric homeostasis

    Fed Proc

    (1984)
  • S.J. Cooper et al.

    Naloxone suppresses fluid consumption in tests of choice between sodium chloride solutions and water in male and female water-deprived rats

    Psychopharmacology

    (1984)
  • E.S. Corp

    The receptor basis of neuropeptide Y-induced food intake

  • Cited by (93)

    • Food intake regulation

      2022, Sturkie's Avian Physiology
    View all citing articles on Scopus
    View full text