Nociceptin receptor

Nociceptin receptor
Opiate receptor-like 1
Symbols OPRL1; KOR-3; MGC34578; NOCIR; OOR; ORL1
External IDs OMIM602548 MGI97440 HomoloGene22609 GeneCards: OPRL1 Gene
Species Human Mouse
Entrez 4987 18389
Ensembl ENSG00000125510 ENSMUSG00000027584
UniProt P41146 Q542U1
RefSeq (mRNA) NM_000913.4 NM_011012.4
RefSeq (protein) NP_000904.1 NP_035142.1
Location (UCSC) Chr 20:
62.71 – 62.73 Mb
Chr 2:
181.45 – 181.46 Mb
PubMed search [1] [2]

The nociceptin receptor or NOP also known as the orphanin FQ receptor or kappa-type 3 opioid receptor is a protein that in humans is encoded by the OPRL1 (opioid receptor-like 1) gene.[1] The nociceptin receptor is a G protein-coupled receptor whose natural ligand is known as nociceptin or orphanin FQ, a 17 amino acid neuropeptide.[2] This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors.[3]



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.[4] Within the central nervous system its action can be either similar or opposite to those of opioids depending on their location.[5] 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.[5]

Selective ligands

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. More recently a range of selective ligands for ORL-1 have been developed, which show little or no affinity to other opioid receptors and so allow ORL-1 mediated responses to be studied in isolation.


  • Buprenorphine (not selective for ORL-1, also partial agonist of µ-opioid and δ-opioid receptors, and competitive antagonist of ϰ-opioid receptors)
  • Nociceptin
  • Norbuprenorphine (not selective for ORL-1, also full agonist at μ-opioid and δ-opioid receptors)
  • NNC 63-0532
  • Ro64-6198
  • Ro65-6570
  • SCH-221,510
  • SR-16435 (mixed mu / nociceptin partial agonist)


  • JTC-801
  • J-113,397
  • SB-612,111
  • SR-16430


ORL 1 agonists are being studied as treatments for heart failure and migraine[6] while nociceptin antagonists such as JTC-801 may have analgesic[7] and antidepressant qualities.[8]

The novel drug buprenorphine is a partial agonist at ORL 1 receptors while its metabolite norbuprenorphine is a full agonist at these receptors.[9]


  1. ^ Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, Caput D, Vassart G, Meunier JC (March 1994). "ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization". FEBS Lett. 341 (1): 33–8. doi:10.1016/0014-5793(94)80235-1. PMID 8137918. 
  2. ^ Henderson G, McKnight AT (August 1997). "The orphan opioid receptor and its endogenous ligand--nociceptin/orphanin FQ". Trends Pharmacol. Sci. 18 (8): 293–300. doi:10.1016/S0165-6147(97)90645-3. PMID 9277133. 
  3. ^ "Entrez Gene: OPRL1 opiate receptor-like 1". 
  4. ^ Liu Z, Wang Y, Zhang J, Ding J, Guo L, Cui D, Fei J (March 2001). "Orphanin FQ: an endogenous antagonist of rat brain dopamine transporter". Neuroreport 12 (4): 699–702. doi:10.1097/00001756-200103260-00017. PMID 11277567. 
  5. ^ a b Calo' G, Guerrini R, Rizzi A, Salvadori S, Regoli D (April 2000). "Pharmacology of nociceptin and its receptor: a novel therapeutic target". Br. J. Pharmacol. 129 (7): 1261–83. doi:10.1038/sj.bjp.0703219. PMC 1571975. PMID 10742280. 
  6. ^ Mørk H, Hommel K, Uddman R, Edvinsson L, Jensen R (September 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. 
  7. ^ Scoto GM, Aricò G, Ronsisvalle S, Parenti C (July 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. 
  8. ^ Redrobe JP, Calo' G, Regoli D, Quirion R (February 2002). "Nociceptin receptor antagonists display antidepressant-like properties in the mouse forced swimming test". Naunyn Schmiedebergs Arch. Pharmacol. 365 (2): 164–7. doi:10.1007/s00210-001-0511-0. PMID 11819035. 
  9. ^ Khroyan TV, Polgar WE, Jiang F, Zaveri NT, Toll L (December 2009). "Nociceptin/orphanin FQ receptor activation attenuates antinociception induced by mixed nociceptin/orphanin FQ/mu-opioid receptor agonists". J. Pharmacol. Exp. Ther. 331 (3): 946–53. doi:10.1124/jpet.109.156711. PMC 2784721. PMID 19713488. 

Further reading

  • Mollereau C, Mouledous L (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.". Neurosignals 11 (4): 197–212. doi:10.1159/000065432. PMID 12393946. 
  • Zaveri N (2003). "Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: research tools and potential therapeutic agents.". Life Sci. 73 (6): 663–78. doi:10.1016/S0024-3205(03)00387-4. PMID 12801588. 
  • Wick MJ, Minnerath SR, Roy S, et al. (1996). "Expression of alternate forms of brain opioid 'orphan' receptor mRNA in activated human peripheral blood lymphocytes and lymphocytic cell lines.". Brain Res. Mol. Brain Res. 32 (2): 342–7. doi:10.1016/0169-328X(95)00096-B. PMID 7500847. 
  • Meunier JC, Mollereau C, Toll L, et al. (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, et al. (1999). "GalphaL1 (Galpha14) couples the opioid receptor-like1 receptor to stimulation of phospholipase C.". J. Pharmacol. Exp. Ther. 288 (1): 232–8. PMID 9862775. 
  • Feild JA, Foley JJ, Testa TT, et al. (1999). "Cloning and characterization of a rabbit ortholog of human Galpha16 and mouse G(alpha)15.". FEBS Lett. 460 (1): 53–6. doi:10.1016/S0014-5793(99)01317-4. PMID 10571060. 
  • Mouledous L, Topham CM, Moisand C, et al. (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.". Mol. Pharmacol. 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 (2000). "A core-promoter region functions bi-directionally for human opioid-receptor-like gene ORL1 and its 5'-adjacent gene GAIP.". J. Mol. Biol. 304 (3): 259–70. doi:10.1006/jmbi.2000.4212. PMID 11090272. 
  • Okada K, Sujaku T, Chuman Y, et al. (2001). "Highly potent nociceptin analog containing the Arg-Lys triple repeat.". Biochem. Biophys. Res. Commun. 278 (2): 493–8. doi:10.1006/bbrc.2000.3822. PMID 11097863. 
  • Serhan CN, Fierro IM, Chiang N, Pouliot M (2001). "Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4.". J. Immunol. 166 (6): 3650–4. PMID 11238602. 
  • Deloukas P, Matthews LH, Ashurst J, et al. (2002). "The DNA sequence and comparative analysis of human chromosome 20.". Nature 414 (6866): 865–71. doi:10.1038/414865a. PMID 11780052. 
  • Mandyam CD, Thakker DR, Christensen JL, Standifer KM (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.". J. Pharmacol. Exp. Ther. 302 (2): 502–9. doi:10.1124/jpet.102.033159. PMID 12130708. 
  • Thakker DR, Standifer KM (2003). "Orphanin FQ/nociceptin blocks chronic morphine-induced tyrosine hydroxylase upregulation.". Brain Res. Mol. Brain Res. 105 (1-2): 38–46. doi:10.1016/S0169-328X(02)00390-X. PMID 12399106. 
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. 
  • Spampinato S, Di Toro R, Alessandri M, Murari G (2003). "Agonist-induced internalization and desensitization of the human nociceptin receptor expressed in CHO cells.". Cell. Mol. Life Sci. 59 (12): 2172–83. doi:10.1007/s000180200016. PMID 12568343. 

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