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An additional opioid receptor has been identified and cloned based on homology with the cDNA. This receptor is known as the nociceptin receptor or NOP receptor. Its natural ligand is known alternately as nociceptin or orphanin FQ.[1]

The protein encoded by this gene is a G protein-coupled receptor whose expression can be induced by phytohemagglutinin. The encoded integral membrane protein is a receptor for the 17 aa neuropeptide nociceptin/orphanin FQ. This gene may be involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. A promoter for this gene also functions as a promoter for another gene, regulator of G-protein signalling 19 (RGS19), located on the opposite strand. Two transcript variants encoding the same protein have been found for this gene.[2]


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


  • Nociceptin
  • Norbuprenorphine (not selective for ORL-1, also full agonist at μ-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. Henderson G, McKnight A (1997). The orphan opioid receptor and its endogenous ligand--nociceptin/orphanin FQ. Trends Pharmacol Sci 18 (8): 293–300.
  2. Entrez Gene: OPRL1 opiate receptor-like 1.
  3. Nociceptin / Orphanin and dopamine. URL accessed on 2007-08-22.
  4. Nociceptin ( Orphanin ). URL accessed on 2007-08-22.
  5. Nociceptin ( Orphanin ). URL accessed on 2007-08-22.
  6. Nociceptin:ORL-1 as a target for analgesia. URL accessed on 2007-08-22.
  7. Scoto GM, Aricò G, Ronsisvalle S, Parenti C. Blockade of the nociceptin/orphanin FQ/NOP receptor system in the rat ventrolateral periaqueductal gray potentiates DAMGO analgesia. Peptides. 2007 Jul;28(7):1441-6. PMID 17628212
  8. Nociceptin antagonists as antidepressants. URL accessed on 2007-08-22.
  9. Psychoactive Drug Mechanisms -- URL accessed on 2007-08-22.

Further reading

  • Mollereau C, Mouledous L (2000). Tissue distribution of the opioid receptor-like (ORL1) receptor.. Peptides 21 (7): 907–17.
  • New DC, Wong YH (2003). The ORL1 receptor: molecular pharmacology and signalling mechanisms.. Neurosignals 11 (4): 197–212.
  • 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.
  • 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.
  • 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.
  • Mollereau C, Parmentier M, Mailleux P, et al. (1994). ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization.. FEBS Lett. 341 (1): 33–8.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Deloukas P, Matthews LH, Ashurst J, et al. (2002). The DNA sequence and comparative analysis of human chromosome 20.. Nature 414 (6866): 865–71.
  • 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.
  • 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.
  • 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.
  • 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.

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