A peptide termed nociceptin/orphanin FQ (N/OFQ) was recently identified as an endogenous agonist for the opioid receptor-like receptor currently specified as NOP receptor. Despite many structural homologies to the opioid system, the NOP receptor shows low-affinity binding to selective opioid agonists or antagonists. Vice versa, N/OFQ selectively activates the NOP receptor but not any opioid receptor subtype. This novel receptor/ligand system is widely expressed in the brain. At the cellular level, the actions of N/OFQ resemble those elicited by opioid peptides. The NOP receptor is coupled to G-proteins, whose activation results in inhibition of adenylate cyclase, modulation of calcium and potassium conductances, and regulation of transmitter systems. At the behavioral level, systemic application of N/OFQ elicits a unique range of responses, including a wide range of effects on pain processing such as hyperalgesia, analgesia, and allodynia, as well as anxiolytic actions, modulation of opioid-mediated processes, and influences on learning and memory. NEUROSCIENTIST 9(2): 158–168, 2003.
Get full access to this article
View all access options for this article.
References
1.
Albrecht D, Bluhdorn R, Siegmund H, Berger H, Calo’ G. 2001. Inhibitory action of nociceptin/orphanin FQ on functionally different thalamic neurons in urethane-anaesthetized rats. Br J Pharmacol134: 333–42.
2.
Allen CN, Jiang ZG, Teshima K, Darland T, Ikeda M, Nelson CS, and others. 1999. Orphanin-FQ/nociceptin (OFQ/N) modulates the activity of suprachiasmatic nucleus neurons. J Neurosci19: 2152–60.
3.
Amano T, Matsubayashi H, Tamura Y, Takahashi T. 2000. Orphanin FQ-induced outward current in rat hippocampus. Brain Res853: 269–74.
4.
Bunzow JR, Saez C, Mortrud M, Bouvier C, Williams JT, Low M, and others. 1994. 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 Lett347: 284–8.
5.
Calo’ G, Guerrini R, Rizzi A, Salvadori S, Regoli D. 2000. Pharmacology of nociceptin and its receptor: a novel therapeutic target. Brit J Pharmacol129: 1261–83.
6.
Calo’ G, Rizzi A, Bigoni R, Guerrini R, Salvadori S, Regoli D. 2002. Pharmacological profile of nociceptin/orphanin FQ receptors. Clin Exp Pharmacol Physiol29: 223–8.
7.
Chen Y, Fan Y, Liu J, Mestek A, Tian M, Kozak CA, and others. 1994. Molecular cloning, tissue distribution and chromosomal localization of a novel member of the opioid receptor gene family. FEBS Lett347: 279–83.
8.
Chu X, Xu N, Li P, Wang JQ. 1999. The nociceptin receptor-mediated inhibition of the rat rostral ventrolateral medulla neurons in vitro. Eur J Pharmacol364: 49–53.
9.
Ciccocioppo R, Angeletti S, Panocka I, Massi M. 2000. Nociceptin/orphanin FQ and drugs of abuse. Peptides21: 1071–80.
10.
Ciccocioppo R, Biondini M, Antonelli L, Wichmann J, Jenck F, Massi M. 2002. Reversal of stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198. Psychopharmacology161: 113–9.
11.
Connor M, Christie MJ. 1998. Modulation of Ca²+ channel currents of acutely dissociated rat periaqueductal grey neurons. J Physiol509: 47–58.
Connor M, Vaughan CW, Chieng B, Christie MJ. 1996. Nociceptin receptor coupling to a potassium conductance in rat locus coeruleus neurones in vitro. Br J Pharmacol119: 1614–8.
14.
Connor M, Vaughan CW, Jennings EA, Allen RG, Christie MJ. 1999. Nociceptin, Phe¹ψ-nociceptin1-13, nocistatin and prepronociceptin154-181 effects on calcium channel currents and a potassium current in rat locus coeruleus in vitro. Br J Pharmacol128: 1779–87.
15.
Cox BM, Chavkin C, Christie MJ, Civelli O, Evans C, Hamon MD, and others. 2000. Opioid receptors. In: Girdlestone D, editor. The IUPHAR compendium of receptor characterization and classification. London: IUPHAR Media Ltd. p 321–33.
16.
Doi N, Dutia MB, Russell JA. 1998. Inhibition of rat oxytocin and vasopressin supraoptic nucleus neurons by nociceptin in vitro. Neuroscience84: 913–21.
17.
Dolphin AC. 1998. Mechanisms of modulation of voltage-dependent calcium channels by G proteins. J Physiol506: 3–11.
18.
Emmerson PJ, Miller RJ. 1999. Pre- and postsynaptic actions of opioid and orphan opioid agonists in the rat arcuate nucleus and ventromedial hypothalamus in vitro. J Physiol517: 431-45.
19.
Eriksson KS, Stevens DR, Haas HL. 2000. Opposite modulation of histaminergic neurons by nociceptin and morphine. Neuropharmacology39: 2492–8.
20.
Faber ES, Chambers JP, Evans RH, Henderson G. 1996. Depression of glutamatergic transmission by nociceptin in the neonatal rat hemisected spinal cord preparation in vitro. Br J Pharmacol119: 189–90.
21.
Fukuda K, Kato S, Mori K, Nishi M, Takeshima H, Iwabe N, and others. 1994. cDNA cloning and regional distribution of a novel member of the opioid receptor family. FEBS Lett343: 42–6.
22.
Gavioli EC, Rae GA, Calo’ G, Guerrini R, De Lima TC. 2002. Central injections of nocistatin or its C-terminal hexapeptide exert anxiogenic-like effect on behaviour of mice in the plus-maze test. Br J Pharmacol136: 764–72.
23.
Griebel G, Perrault G, Sanger DJ. 1999. Orphanin FQ, a novel neuropeptide with anti-stress-like activity. Brain Res836: 221–4.
24.
Grisel JE, Mogil JS. 2000. Effects of supraspinal orphanin FQ/nociceptin. Peptides21: 1037–45.
25.
Harrison LM, Grandy DK. 2000. Opiate modulating properties of nociceptin/orphanin FQ. Peptides21: 151–72.
26.
Hawes BE, Graziano MP, Lambert DG. 2000. Cellular actions of nociceptin: transduction mechanisms. Peptides21: 961–7.
27.
Heinricher MM, McGaraughty S, Grandy DK. 1997. Circuitry underlying antiopioid actions of orphanin FQ in the rostral ventromedial medulla. J Neurophysiol78: 3351–8.
28.
Higgins GA, Kew JN, Richards JG, Takeshima H, Jenck F, Adam G, and others. 2002. A combined pharmacological and genetic approach to investigate the role of orphanin FQ in learning and memory. Eur J Neurosci15: 911–22.
29.
Hiramatsu M, Inoue K. 2000. Improvement by low doses of nociceptin on scopolamine-induced impairment of learning and/or memory. Eur J Pharmacol395: 149–56.
30.
Ho MK, New DC, Wong YH. 2002. Co-expressions of different opioid receptor types differentially modulate their signaling via G(16). Neurosignals11: 115–22.
31.
Houtani T, Nishi M, Takeshima H, Nukada T, Sugimoto T. 1996. Structure and regional distribution of nociceptin/orphanin FQ precursor. Biochem Biophys Res Commun219: 714–9.
32.
Ikeda K, Kobayashi K, Kobayashi T, Ichikawa T, Kumanishi T, Kishida H, and others. 1997. Functional coupling of the nociceptin/orphanin FQ receptor with the G-protein-activated K+ (GIRK) channel. Brain Res Mol Brain Res45: 117–26.
33.
Jenck F, Ouagazzal AM, Pauly-Evers M, Moreau JL. 2000. OrphaninFQ: role in behavioral fear responses and vulnerability to stress? Mol Psychiatry5: 572–4.
34.
Knoflach F, Reinscheid RK, Civelli O, Kemp JA. 1996. Modulation of voltage-gated calcium channels by orphanin FQ in freshly dissociated hippocampal neurons. J Neurosci16: 6657–64.
35.
Köster A, Montkowski A, Schulz S, Stube EM, Knaudt K, Jenck F, and others. 1999. Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice. Proc Natl Acad Sci USA96: 10444–9.
36.
Kubo Y. 2000. Overview of potassium channel families: molecular bases of the functional diversity. In: Endo M, Kurachi Y, Mishina M, editors. Handbook of experimental pharmacology, Vol. 147. Pharmacology of ionic channel function: activators and inhibitors. Berlin-Heidelberg: Springer. p 157–76.
37.
Lachowicz JE, Shen Y, Monsma FJ, Sibley DR. 1995. Molecular cloning of a novel G protein-coupled receptor related to the opiate receptor family. J Neurochem64: 34–40.
38.
Lai CC, Wu SY, Dun SL, Dun NJ. 1997. Nociceptin-like immunoreactivity in the rat dorsal horn and inhibition of substantia gelatinosa neurons. Neuroscience81: 887–91.
39.
Lee K, Nicholson JR, McKnight AT. 1997. Nociceptin hyperpolarises neurones in the rat ventromedial hypothalamus. Neurosci Lett239: 37–40.
40.
Liebel JT, Swandulla D, Zeilhofer HU. 1997. Modulation of excitatory synaptic transmission by nociceptin in superficial dorsal horn neurones of the neonatal rat spinal cord. Br J Pharmacol121: 425–32.
41.
Luo C, Kumamoto E, Furue H, Chen J, Yoshimura M. 2002. Nociceptin inhibits excitatory but not inhibitory transmission to substantia gelatinosa neurones of adult rat spinal cord. Neuroscience109: 349–58.
42.
Luo C, Kumamoto E, Furue H, Yoshimura M. 2001. Nociceptin-induced outward current in substantia gelatinosa neurones of the adult rat spinal cord. Neuroscience108: 323–30.
43.
Madamba SG, Schweitzer P, Siggins GR. 1999. Nociceptin augments K+ currents in hippocampal CA1 neurons by both ORL-1 and opiate receptor mechanisms. J Neurophysiol82: 1776–85.
44.
Mamiya T, Noda Y, Nishi M, Takeshima H, Nabeshima T. 1998. Enhancement of spatial attention in nociceptin/orphanin FQ receptor-knockout mice. Brain Res783: 236–40.
45.
Meis S, Munsch T, Pape HC. 2002. Antioscillatory effects of nociceptin/orphanin FQ in synaptic networks of the rat thalamus. J Neurosci22: 718–27.
46.
Meis S, Pape HC. 1998. Postsynaptic mechanisms underlying responsiveness of amygdaloid neurons to nociceptin/orphanin FQ. J Neurosci18: 8133–44.
47.
Meis S, Pape HC. 2001. Control of glutamate and GABA release by nociceptin/orphanin FQ in the rat lateral amygdala. J Physiol532: 701–12.
48.
Meunier J-C, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, and others. 1995. Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature377: 532–5.
49.
Meunier J, Mouledous L, Topham CM. 2000. The nociceptin (ORL1) receptor: molecular cloning and functional architecture. Peptides21: 893–900.
50.
Miller RJ. 1998. Presynaptic receptors. Annu Rev Pharmacol Toxicol38: 201–27.
51.
Mogil JS, Pasternak GW. 2001. The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol Rev53: 381–415.
52.
Mollereau C, Mouledous L. 2000. Tissue distribution of the opioid receptor-like (ORL1) receptor. Peptides21: 907–17.
53.
Mollereau C, Parmentier M, Mailleux P, Butour J-L, Moisand C, Chalon P, and others. 1994. ORL1, a novel member of the opioid receptor family: cloning, functional expression and localization. FEBS Lett341: 33–8.
54.
Mollereau C, Simons MJ, Soularue P, Liners F, Vassart G, Meunier JC, and others. 1996. Structure, tissue distribution, and chromosomal localization of the prepronociceptin gene. Proc Natl Acad Sci USA93: 8666–70.
55.
Moran TD, Abdulla FA, Smith PA. 2000. Cellular neurophysiological actions of nociceptin/orphanin FQ. Peptides21: 969–76.
56.
Narayanan S, Lutfy K, Maidment N. 2002. Sensitization to cocaine after a single intra-cerebral injection of orphanin FQ/nociceptin. Behav Brain Res131: 97–103.
57.
Neal CR Jr, Mansour A, Reinscheid R, Nothacker HP, Civelli O, Watson SJ Jr. 1999. Localization of orphanin FQ (nociceptin) peptide and messenger RNA in the central nervous system of the rat. J Comp Neurol406: 503–47.
58.
Nishi M, Houtani T, Noda Y, Mamiya T, Sato K, Doi T, and others. 1997. Unrestrained nociceptive response and disregulation of hearing ability in mice lacking the nociceptin/orphaninFQ receptor. EMBO J16: 1858–64.
59.
Nishi M, Takeshima H, Mori M, Nakagawara K, Takeuchi T. 1994. Structure and chromosomal mapping of genes for the mouse kappa-opioid receptor and an opioid receptor homologue (MOR-C). Biochem Biophys Res Commun205: 1353–7.
60.
Noda Y, Mamiya T, Manabe T, Nishi M, Takeshima H, Nabeshima T. 2000. Role of nociceptin systems in learning and memory. Peptides21: 1063–9.
61.
Nothacker H-P, Reinscheid RK, Mansour A, Henningsen RA, Ardati A, Monsma FJ, and others. 1996. Primary structure and tissue distribution of the orphanin FQ precursor. Proc Natl Acad Sci USA93: 8677–82.
62.
Okuda-Ashitaka E, Ito S. 2000. Nocistatin: a novel neuropeptide encoded by the gene for the nociceptin/orphanin FQ precursor. Peptides21: 1101–9.
63.
Okuda-Ashitaka E, Minami T, Tachibana S, Yoshihara Y, Nishiuchi Y, Kimura T, and others. 1998. Nocistatin, a peptide that blocks nociceptin action in pain transmission. Nature392: 286–9.
64.
Okuda-Ashitaka E, Tachibana S, Houtani T, Minami T, Masu Y, Nishi M, and others. 1996. Identification and characterization of an endogenous ligand for opioid receptor homologue ROR-C: its involvement in allodynic response to innocuous stimulus. Brain Res Mol Brain Res43: 96–104.
65.
Olianas MC, Onali P. 2002. Pharmacological properties of nociceptin/orphanin FQ-induced stimulation and inhibition of cyclic AMP formation in distinct layers of rat olfactory bulb. Br J Pharmacol135: 233–8.
66.
Onali P, Ingianni A, Olianas MC. 2001. Dual coupling of opioid receptor-like (ORL1) receptors to adenylyl cyclase in the different layers of the rat main olfactory bulb. J Neurochem77: 1520–30.
67.
Pan Y-X, Cheng J, Xu J, Pasternak GW. 1994. Cloning, expression and classification of a kappa3-related opioid receptor using antisense oligodeoxynucleotides. Regul Pept54: 217–8.
68.
Pan Y-X, Xu J, Pasternak GW. 1996. Cloning and expression of a cDNA encoding a mouse brain orphanin FQ/nociceptin precursor. Biochem J315: 11–3.
69.
Pan Z, Hirakawa N, Fields HL. 2000. A cellular mechanism for the bidirectional pain-modulating actions of orphanin FQ/nociceptin. Neuron26: 515–22.
70.
Polidori C, de Caro G, Massi M. 2000. The hyperphagic effect of nociceptin/orphanin FQ in rats. Peptides21: 1051–62.
71.
Redrobe JP, Calo’ G, Guerrini R, Regoli D, Quirion R. 2000. [Nphe(1)]-Nociceptin (1-13)-NH(2), a nociceptin receptor antagonist, reverses nociceptin-induced spatial memory impairments in the Morris water maze task in rats. Br J Pharmacol131: 1379–84.
72.
Reinscheid RK, Nothacker H-P, Bourson A, Ardati A, Henningsen RA, Bunzow JR, and others. 1995. Orphanin FQ: a neuropeptide that activates an opioid like G protein-coupled receptor. Science270: 792–4.
73.
Reinscheid RK, Nothacker H, Civelli O. 2000. The orphanin FQ/nociceptin gene: structure, tissue distribution of expression and functional implications obtained from knockout mice. Peptides21: 901–6.
74.
Rizzi A, Bigoni R, Marzola G, Guerrini R, Salvadori S, Regoli D, and others. 2001. Characterization of the locomotor activity-inhibiting effect of nociceptin/orphanin FQ in mice. Naunyn Schmiedebergs Arch Pharmacol363: 161–5.
75.
Roumy M, Zajac J. 1999. Neuropeptide FF selectively attenuates the effects of nociceptin on acutely dissociated neurons of the rat dorsal raphe nucleus. Brain Res845: 208–14.
76.
Roumy M, Zajac JM. 2001. Neuropeptide FF receptors couple to a cholera toxin-sensitive G-protein in rat dorsal raphe neurones. Eur J Pharmacol417: 45–9.
77.
Saito Y, Maruyama K, Saido TC, Kawashima S. 1995. N23K, a gene transiently up-regulated during neural differentiation, encodes a precursor protein for a newly identified neuropeptide nociceptin. Biochem Biophys Res Commun217: 539–45.
78.
Sandin J, Georgieva J, Schott PA, Ogren SO, Terenius L. 1997. Nociceptin/orphanin FQ microinjected into hippocampus impairs spatial learning in rats. Eur J Neurosci9: 194–7.
79.
Schlicker E, Morari M. 2000. Nociceptin/orphanin FQ and neurotransmitter release in the central nervous system. Peptides21: 1023–9.
80.
Shirasaka T, Miyahara S, Takasaki M, Kannan H. 2001. Nociceptin/orphanin FQ and [Phe¹ψ(CH2-NH)Gly²]nociceptin(1-13)NH2 modulates the activity of hypothalamic paraventricular nucleus neurons in vitro. Brain Res890: 147–53.
81.
Slugg RM, Ronnekleiv OK, Grandy DK, Kelly MJ. 1999. Activation of an inwardly rectifying K+ conductance by orphanin-FQ/nociceptin in vasopressin-containing neurons. Neuroendocrinology69: 385–96.
82.
Stanfa LC, Chapman V, Kerr N, Dickenson AH. 1996. Inhibitory action of nociceptin on spinal dorsal horn neurones of the rat, in vivo. Br J Pharmacol118: 1875–7.
83.
Tallent MK, Madamba SG, Siggins GR. 2001. Nociceptin reduces epileptiform events in CA3 hippocampus via presynaptic and postsynaptic mechanisms. J Neurosci21: 6940–8.
84.
Terenius L, Sandin J, Sakurada T. 2000. Nociceptin/orphanin FQ metabolism and bioactive metabolites. Peptides21: 919–22.
85.
Thomson AM. 2000. Facilitation, augmentation and potentiation at central synapses. Trends Neurosci23: 305–12.
86.
Vaughan CW, Christie MJ. 1996. Increase by the ORL1 receptor (opioid receptor-like1) ligand, nociceptin, of inwardly rectifying K conductance in dorsal raphe nucleus neurones. Br J Pharmacol117: 1609–11.
87.
Vaughan CW, Connor M, Jennings EA, Marinelli S, Allen RG, Christie MJ. 2001. Actions of nociceptin/orphanin FQ and other prepronociceptin products on rat rostral ventromedial medulla neurons in vitro. J Physiol534: 849–59.
88.
Vaughan CW, Ingram SL, Christie MJ. 1997. Actions of the ORL1 receptor ligand nociceptin on membrane properties of rat periaqueductal gray neurons in vitro. J Neurosci17: 996–1003.
89.
Wagner EJ, Ronnekleiv OK, Grandy DK, Kelly MJ. 1998. The peptide orphanin FQ inhibits β-endorphin neurons and neurosecretory cells in the hypothalamic arcuate nucleus by activating an inwardly-rectifying K+ conductance. Neuroendocrinology67: 73–82.
90.
Wang JB, Johnson PS, Imai Y, Persico AM, Ozenberger BA, Eppler CM, and others. 1994. cDNA cloning of an orphan opiate receptor gene family member and its splice variant. FEBS Lett348: 75–9.
91.
Wick MJ, Minnerath SR, Lin X, Elde R, Law P-Y, Loh HH. 1994. Isolation of a novel cDNA encoding a putative membrane receptor with high homology to the cloned μ, δ, and κ opioid receptors. Mol Brain Res27: 37–44.
92.
Yu TP, Fein J, Phan T, Evans CJ, Xie CW. 1997. Orphanin FQ inhibits synaptic transmission and long-term potentiation in rat hippocampus. Hippocampus7: 88–94.
93.
Yu TP, Xie CW. 1998. Orphanin FQ/nociceptin inhibits synaptic transmission and long-term potentiation in rat dentate gyrus through postsynaptic mechanisms. J Neurophysiol80: 1277–84.
94.
Zeilhofer HU, Selbach UM, Guhring H, Erb K, Ahmadi S. 2000. Selective suppression of inhibitory synaptic transmission by nocistatin in the rat spinal cord dorsal horn. J Neurosci20: 4922–9.
95.
Zheng F, Grandy DK, Johnson SW. 2002. Actions of orphanin FQ/nociceptin on rat ventral tegmental area neurons in vitro. Br J Pharmacol136: 1065–71.
