Nociceptin receptor

Available structures
PDBOrtholog search: PDBe RCSB
Aliases OPRL1, KOR-3, NOCIR, OOR, ORL1, NOP, NOPr, opioid related nociceptin receptor 1
External IDs OMIM: 602548 MGI: 97440 HomoloGene: 22609 GeneCards: OPRL1
Targeted by Drug
cebranopadol, nociceptin, Ro64-6198, j-113397, jtc-801 free base, SB 612111[1]
Species Human Mouse









RefSeq (mRNA)
RefSeq (protein)


Location (UCSC) Chr 20: 64.08 – 64.1 Mb Chr 2: 181.72 – 181.72 Mb
PubMed search [2] [3]
View/Edit HumanView/Edit Mouse

The nociceptin receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 (opioid receptor-like 1) gene.[4] The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ).[5] This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors.[6]

Although NOP shares high sequence identity (~60%) with the ‘classical’ opioid receptors μ-OR (MOR), κ-OR (KOR), and δ-OR (DOR), it possesses little or no affinity for opioid peptides or morphine-like compounds.[7] Likewise, classical opioid receptors possess little affinity towards NOP’s endogenous ligand nociceptin, which is structurally related to dynorphin A.[7]


Nociceptin is thought to be an endogenous antagonist of dopamine transport that may act either directly on dopamine or by inhibiting GABA to affect dopamine levels.[8] Within the central nervous system its action can be either similar or opposite to those of opioids depending on their location.[9] It controls a wide range of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites.[9]


Several commonly used opioid drugs including etorphine and buprenorphine have been demonstrated to bind to nociceptin receptors, but this binding is relatively insignificant compared to their activity at other opioid receptors in the acute setting (however the non-analgesic NOPr antagonist SB-612,111 was demonstrated to potentiate the therapeutic benefits of morphine). Chronic administration of nociceptin receptor agonists results in an attentuation of the analgesic and anti-allodynic effects of opiates; this mechanism inhibits the action of endogenous opioids as well, resulting in an increase in pain severity, depression, and both physical and psychological opiate dependence following chronic NOPr agonist administration.[10] Administration of the NOPr antagonist SB-612,111 has been shown to inhibit this process.[11] More recently a range of selective ligands for NOP have been developed, which show little or no affinity to other opioid receptors and so allow NOP-mediated responses to be studied in isolation.




NOP agonists are being studied as treatments for heart failure and migraine[14] while nociceptin antagonists such as JTC-801 may have analgesic[15] and antidepressant qualities.[16]


  1. "Drugs that physically interact with Nociceptin receptor view/edit references on wikidata".
  2. "Human PubMed Reference:".
  3. "Mouse PubMed Reference:".
  4. Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, Caput D, Vassart G, Meunier JC (Mar 1994). "ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization". FEBS Letters. 341 (1): 33–8. doi:10.1016/0014-5793(94)80235-1. PMID 8137918.
  5. Henderson G, McKnight AT (Aug 1997). "The orphan opioid receptor and its endogenous ligand--nociceptin/orphanin FQ". Trends in Pharmacological Sciences. 18 (8): 293–300. doi:10.1016/S0165-6147(97)90645-3. PMID 9277133.
  6. "Entrez Gene: OPRL1 opiate receptor-like 1".
  7. 1 2 Butour JL, Moisand C, Mazarguil H, Mollereau C, Meunier JC (1997). "Recognition and activation of the opioid receptor-like ORL 1 receptor by nociceptin, nociceptin analogs and opioids". European Journal of Pharmacology. 321 (1): 97–103. doi:10.1016/S0014-2999(96)00919-3. PMID 9083791.
  8. Liu Z, Wang Y, Zhang J, Ding J, Guo L, Cui D, Fei J (Mar 2001). "Orphanin FQ: an endogenous antagonist of rat brain dopamine transporter". NeuroReport. 12 (4): 699–702. doi:10.1097/00001756-200103260-00017. PMID 11277567.
  9. 1 2 Calo' G, Guerrini R, Rizzi A, Salvadori S, Regoli D (Apr 2000). "Pharmacology of nociceptin and its receptor: a novel therapeutic target". British Journal of Pharmacology. 129 (7): 1261–83. doi:10.1038/sj.bjp.0703219. PMC 1571975Freely accessible. PMID 10742280.
  10. Khroyan TV, Polgar WE, Orduna J, Montenegro J, Jiang F, Zaveri NT, Toll L. (22 Aug 2011). "Differential effects of nociceptin/orphanin FQ (NOP) receptor agonists in acute versus chronic pain: studies with bifunctional NOP/μ receptor agonists in the sciatic nerve ligation chronic pain model in mice.". Journal of Pharmacology and Experimental Therapeutics. 339: 687–93. doi:10.1124/jpet.111.184663. PMC 3199991Freely accessible. PMID 21859931.
  11. Zaratin, PF; Petrone, G; Sbacchi, M; Garnier, M; Fossati, C; Petrillo, P; Ronzoni, S; Giardina, GA; Scheideler, MA (2004). "Modification of nociception and morphine tolerance by the selective opiate receptor-like orphan receptor antagonist (−)-cis-1-methyl-7-4-(2,6-dichlorophenyl)piperidin-1-ylmethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111)". The Journal of Pharmacology and Experimental Therapeutics. 308 (2): 454–61. doi:10.1124/jpet.103.055848. PMID 14593080.
  12. Huiping Ding, Paul W. Czoty, Norikazu Kiguchi, Gerta Cami-Kobeci, Devki D. Sukhtankar, Michael A. Nader, Stephen M. Husbands, and Mei-Chuan Ko, "A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates." Proc. Natl. Acad. Sci. USA August 29, 2016 0:1605295113v1-201605295
  13. Hirao A, Imai A, Sugie Y, Yamada Y, Hayashi S, Toide K (Mar 2008). "Pharmacological characterization of the newly synthesized nociceptin/orphanin FQ-receptor agonist 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole as an anxiolytic agent". Journal of Pharmacological Sciences. 106 (3): 361–8. doi:10.1254/jphs.fp0071742. PMID 18319566.
  14. Mørk H, Hommel K, Uddman R, Edvinsson L, Jensen R (Sep 2002). "Does nociceptin play a role in pain disorders in man?". Peptides. 23 (9): 1581–7. doi:10.1016/S0196-9781(02)00101-8. PMID 12217418.
  15. Scoto GM, Aricò G, Ronsisvalle S, Parenti C (Jul 2007). "Blockade of the nociceptin/orphanin FQ/NOP receptor system in the rat ventrolateral periaqueductal gray potentiates DAMGO analgesia". Peptides. 28 (7): 1441–6. doi:10.1016/j.peptides.2007.05.013. PMID 17628212.
  16. Redrobe JP, Calo' G, Regoli D, Quirion R (Feb 2002). "Nociceptin receptor antagonists display antidepressant-like properties in the mouse forced swimming test". Naunyn-Schmiedeberg's Archives of Pharmacology. 365 (2): 164–7. doi:10.1007/s00210-001-0511-0. PMID 11819035.

Further reading

  • Mollereau C, Mouledous L (Jul 2000). "Tissue distribution of the opioid receptor-like (ORL1) receptor". Peptides. 21 (7): 907–17. doi:10.1016/S0196-9781(00)00227-8. PMID 10998524. 
  • New DC, Wong YH (2003). "The ORL1 receptor: molecular pharmacology and signalling mechanisms". Neuro-Signals. 11 (4): 197–212. doi:10.1159/000065432. PMID 12393946. 
  • Zaveri N (Jun 2003). "Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: research tools and potential therapeutic agents". Life Sciences. 73 (6): 663–78. doi:10.1016/S0024-3205(03)00387-4. PMID 12801588. 
  • Wick MJ, Minnerath SR, Roy S, Ramakrishnan S, Loh HH (Sep 1995). "Expression of alternate forms of brain opioid 'orphan' receptor mRNA in activated human peripheral blood lymphocytes and lymphocytic cell lines". Brain Research. Molecular Brain Research. 32 (2): 342–7. doi:10.1016/0169-328X(95)00096-B. PMID 7500847. 
  • Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P, Monsarrat B (Oct 1995). "Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor". Nature. 377 (6549): 532–5. doi:10.1038/377532a0. PMID 7566152. 
  • Yung LY, Joshi SA, Chan RY, Chan JS, Pei G, Wong YH (Jan 1999). "GalphaL1 (Galpha14) couples the opioid receptor-like1 receptor to stimulation of phospholipase C". The Journal of Pharmacology and Experimental Therapeutics. 288 (1): 232–8. PMID 9862775. 
  • Feild JA, Foley JJ, Testa TT, Nuthulaganti P, Ellis C, Sarau HM, Ames RS (Oct 1999). "Cloning and characterization of a rabbit ortholog of human Galpha16 and mouse G(alpha)15". FEBS Letters. 460 (1): 53–6. doi:10.1016/S0014-5793(99)01317-4. PMID 10571060. 
  • Mouledous L, Topham CM, Moisand C, Mollereau C, Meunier JC (Mar 2000). "Functional inactivation of the nociceptin receptor by alanine substitution of glutamine 286 at the C terminus of transmembrane segment VI: evidence from a site-directed mutagenesis study of the ORL1 receptor transmembrane-binding domain". Molecular Pharmacology. 57 (3): 495–502. PMID 10692489. 
  • Yung LY, Tsim KW, Pei G, Wong YH (2000). "Immunoglobulin G1 Fc fragment-tagged human opioid receptor-like receptor retains the ability to inhibit cAMP accumulation". Biological Signals and Receptors. 9 (5): 240–7. doi:10.1159/000014645. PMID 10965058. 
  • Ito E, Xie G, Maruyama K, Palmer PP (Dec 2000). "A core-promoter region functions bi-directionally for human opioid-receptor-like gene ORL1 and its 5'-adjacent gene GAIP". Journal of Molecular Biology. 304 (3): 259–70. doi:10.1006/jmbi.2000.4212. PMID 11090272. 
  • Okada K, Sujaku T, Chuman Y, Nakashima R, Nose T, Costa T, Yamada Y, Yokoyama M, Nagahisa A, Shimohigashi Y (Nov 2000). "Highly potent nociceptin analog containing the Arg-Lys triple repeat". Biochemical and Biophysical Research Communications. 278 (2): 493–8. doi:10.1006/bbrc.2000.3822. PMID 11097863. 
  • Serhan CN, Fierro IM, Chiang N, Pouliot M (Mar 2001). "Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4". Journal of Immunology. 166 (6): 3650–4. doi:10.4049/jimmunol.166.6.3650. PMID 11238602. 
  • Mandyam CD, Thakker DR, Christensen JL, Standifer KM (Aug 2002). "Orphanin FQ/nociceptin-mediated desensitization of opioid receptor-like 1 receptor and mu opioid receptors involves protein kinase C: a molecular mechanism for heterologous cross-talk". The Journal of Pharmacology and Experimental Therapeutics. 302 (2): 502–9. doi:10.1124/jpet.102.033159. PMID 12130708. 
  • Thakker DR, Standifer KM (Sep 2002). "Orphanin FQ/nociceptin blocks chronic morphine-induced tyrosine hydroxylase upregulation". Brain Research. Molecular Brain Research. 105 (1-2): 38–46. doi:10.1016/S0169-328X(02)00390-X. PMID 12399106. 
  • Spampinato S, Di Toro R, Alessandri M, Murari G (Dec 2002). "Agonist-induced internalization and desensitization of the human nociceptin receptor expressed in CHO cells". Cellular and Molecular Life Sciences. 59 (12): 2172–83. doi:10.1007/s000180200016. PMID 12568343. 

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