Regular paperThe hyperphagic effect of nociceptin/orphanin FQ in rats.
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)
- et al.
Distribution of the nociceptin and nocistatin precursor transcript in the mouse central nervous system
Neuroscience
(1999) - et al.
Suppression of deprivation-induced food and water intake in rats and mice by naloxone
Pharmacol Biochem Behav
(1979) - et al.
Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a μ, Δ or κ opioid receptor type
FEBS Lett
(1994) - et al.
[Phe1psi(CH2-NH)Gly2]-nociceptin-(1–13)NH2 is an agonist of the nociceptin (ORL1) receptor
Eur J Pharmacol
(1998) - et al.
Molecular cloning, tissue distribution and chromosomal localization of a novel member of the opioid receptor gene family
FEBS Lett
(1994) - et al.
Endorphins and food intakekappa opioid receptor agonists and hyperphagia
Pharmacol Biochem Behav
(1985) - et al.
Orphanin FQ/nociceptin. A role in pain and analgesia, but so much more
Trends Neurosci
(1998) - et al.
Naloxone reduces the feeding evoked by intracerebroventricular galanin injection
Physiol Behav
(1994) - et al.
cDNA cloning and regional distribution of a novel member of the opioid receptor family
FEBS Lett
(1994) - et al.
Effects of the opioid antagonist naltrexone on feeding induced by DAMGO in the central nucleus of the amygdala and in the paraventricular nucleus in the rat
Brain Res
(1998)
Stimulation of food intake by muscimol and beta endorphin
Neuropharmacology
[Phe1psi(CH2-NH)Gly2]-nociceptin-(1–13)NH2 acts as an agonist of the orphanin FQ/nociceptin receptor in vivo
Eur J Pharmacol
Structure and regional distribution of nociceptin/orphanin FQ precursor
Biochem Biophys Res Commun
Targeted disruption of the melanocortin-4-receptor results in obesity in mice
Cell
Feeding and body weight regulation by hypothalamic neuropeptides—mediation of the actions of leptin
Trends Neurosci
Endogenous opioids may be involved in idazoxan-induced food intake
Neuropharmacology
Selective antagonist for the melanocortin-4 receptor (HS014) increases food intake in free-feeding rats
Biochem Biophys Res Commun
Anatomy of the CNS opioid systems
Trends Neurosci
Analysis of the ACTH/β-End/α-MSH-immunoreactive afferent input to the hypothalamic paraventricular nucleus of the rat
Brain Res
Alterations in deprivation, glucoprivic and sucrose intake following general, mu and kappa opioid antagonists in the hypothalamic paraventricular nucleus of rats
Neuroscience
Comparison of the structure-activity relationships of nociceptin and dynorphin A using chimeric peptides
FEBS Lett
Orphan opioid receptor antisense probes block orphanin FQ-induced hyperphagia
Eur J Pharmacol
Neuropeptide Ya potent inducer of consummatory behavior in rats
Peptides
Nociceptin/orphanin FQ, and the opioid receptor-like ORL1 receptor
Eur J Pharmacol
ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization
FEBS Lett
Dynorphin-(1–13) induces spontaneous feeding in rats
Life Sci
ACTH-(1–24) and α-MSH antagonize feeding behavior stimulated by kappa opiate agonists
Peptides
Neuropeptide Y receptor(s) mediating feeding in the ratcharacterization with antagonists
Peptides
Structures that delineate orphanin FQ and dynorphin-A pharmacological selectivities
J Biol Chem
Over-consumption of preferred foods following capsaicin pretreatment of the area postrema and adjacent nucleus of the solitary tract
Brain Res
Naloxone inhibits diazepam-induced feeding in rats
Life Sci
Blockade of GABAA receptors in the medial ventral pallidum elicits feeding in satiated rats
Brain Res
Specific changes in food intake elicited by blockade or activation of glutamate receptors in the nucleus accumbens shell
Behav Brain Res
Neuropeptide Y distribution in the rat brain
Science
Orphanin-FQ/nociceptin (OFQ/N) modulates the activity of suprachiasmatic nucleus neurons
J Neurosci
Immunohistochemical localization of ORL-1 in the central nervous system of the rat
J Comp Neurol
Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus
Diabetes
Leptin sensitive neurons in the hypothalamus
Horm Metab Res
Feeding induced by GABAA receptor stimulation within the nucleus accumbens shellregional mapping and characterization of macronutrient and taste preference
Behav Neurosci
Characterization of nociceptin receptors in the peripheryin vitro and in vivo studies
Naunyn-Schmiedeberg’s Arch Pharmacol
Pharmacological characterization of nociceptin receptoran in vitro study
Can J Physiol Pharmacol
Pharmacological characterization of the nociceptin receptor mediating hyperalgesia in the mouse tail withdrawal assay
Br J Pharmacol
Prolonged effects of centrally administered nociceptin in the rat
Regul Pept
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
α-Melanocyte stimulating hormone in the modulation of host reactions
Endocr Rev
Area postremapart of the autonomic circuitry of caloric homeostasis
Fed Proc
Naloxone suppresses fluid consumption in tests of choice between sodium chloride solutions and water in male and female water-deprived rats
Psychopharmacology
The receptor basis of neuropeptide Y-induced food intake
Cited by (93)
Food intake regulation
2022, Sturkie's Avian PhysiologyNociceptin/orphanin FQ receptors modulate the discriminative stimulus effects of oxycodone in C57BL/6 mice
2018, Drug and Alcohol DependenceNociceptin receptor antagonist SB 612111 decreases high fat diet binge eating
2016, Behavioural Brain Research