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Gene Review

OPRL1  -  opiate receptor-like 1

Homo sapiens

Synonyms: KOR-3, Kappa-type 3 opioid receptor, NOCIR, Nociceptin receptor, OOR, ...
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Disease relevance of OPRL1

  • A 60-min activation of mu-or opioid receptor-like 1 (ORL1) opioid receptors natively expressed in BE(2)-C human neuroblastoma cells desensitized both mu- and ORL1 receptor-mediated inhibition of cAMP accumulation [1].
  • In most tissues and cells the opioid receptor-like (ORL1) receptor regulates effectors primarily through the pertussis toxin (PTX)-sensitive guanine nucleotide-binding regulatory proteins (G proteins) Gi/Go [2].
  • Functional expression, activation and desensitization of opioid receptor-like receptor ORL1 in neuroblastoma x glioma NG108-15 hybrid cells [3].
  • The present data demonstrated that astrocyte activation and enhanced cytokine expression at the CNS had a role in eliciting behavioral hypersensitivity; the anti-nociception function of N/OFQ might be dependent on cytokines derived from astrocytes, the effects were attributable to the ORL1 receptor pathway [4].
  • In air-free aqueous solutions, ROOH photosensitization always gave rise to a mixture of hydroxyl and peroxyl radical (*OOR) adducts in varying molar ratios [5].

Psychiatry related information on OPRL1


High impact information on OPRL1


Chemical compound and disease context of OPRL1


Biological context of OPRL1

  • The transcription and alternative splicing of human ORL1 are controlled by two alternate promoters, located approximately 10 kb apart [13].
  • Two different repeat sequence polymorphisms are found in the ORL1 promoter regions [13].
  • A potential ATG codon upstream of the initiation codon of ORL1 starts a new open-reading frame encoding a theoretical polypeptide of 205 amino acid residues [13].
  • The first exons of ORL1 and GAIP are separated by only 83 bp [13].
  • To better understand opioid receptor-like 1 (ORL1) internalization, we fused the C terminus of ORL1, the nociceptin (noc) receptor, to the N terminus of a green fluorescent protein and used the fusion protein to characterize receptor endocytosis in live human embryonic kidney cells [14].

Anatomical context of OPRL1


Associations of OPRL1 with chemical compounds

  • Indeed, there is tremendous interest in the pharmaceutical industry in the development of nonpeptide ligands such as the potent ORL1 agonist, Ro 64-6198, as anxiolytics and the ORL1 antagonist JTC-801 as novel analgesics [6].
  • Alanine mutation, in the human ORL1 receptor, of transmembrane amino acid residues that are conserved in opioid receptors, Asp(130) and Tyr(131) in transmembrane segment (TM) III, Phe(220) and Phe(224) in TM V, and Trp(276) in TM VI, yields mutant receptors with reduced affinity, and proportionally decreased reactivity, toward nociceptin [18].
  • 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 [18].
  • Antisense, but not sense, DNA selectively targeting GRK2 or GRK3 blocks DAMGO-mediated mu- and ORL1 desensitization, respectively [1].
  • To allow the rapid identification of agonists and antagonists, a reporter gene assay has been established in which the ORL1 receptor is functionally linked to the cyclic AMP-dependent expression of luciferase [19].

Physical interactions of OPRL1

  • These compounds were tested for binding affinity using [3H]N/OFQ binding to human ORL1 in CHO cells, and functional activity by measuring stimulation of [35S]GTPgammaS binding in CHO cell membranes [20].
  • In oocytes from Xenopus laevis, NOX 2149 showed an antagonistic effect to the N/OFQ-ORL 1 receptor system that was functionally coupled with G-protein-regulated inwardly rectifying K(+) channels [21].

Regulatory relationships of OPRL1

  • Our results demonstrate for the first time the involvement of conventional PKC isozymes in OFQ/N-induced mu-ORL1 cross-talk, and represent a possible mechanism for OFQ/N-induced anti-opioid actions [22].
  • Prolonged (24 h) activation of the mu receptor desensitized both mu and ORL1 receptor-mediated inhibition of forskolin-stimulated cAMP accumulation and upregulated GRK2 levels in SH-SY5Y and BE(2)-C cells [16].
  • As anticipated, nociceptin receptor activation inhibits the formation of cAMP formation via a pertussis toxin-sensitive G-protein [23].

Other interactions of OPRL1

  • A core-promoter region functions bi-directionally for human opioid-receptor-like gene ORL1 and its 5'-adjacent gene GAIP [13].
  • Reduction of GRK2 and GRK3 levels by antisense, but not sense DNA treatment blocks ORL1 and mu receptor desensitization [22].
  • Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the opioid receptor-like receptor or nociceptin receptor (NOP) [24].
  • Activation of mu or ORL1 receptors in these cells in turn activates extracellular signal-regulated protein kinases (ERKs), ERK1 and ERK2 [25].
  • Coupling to both Gz and G16 was expected because close relatives of the ORL1 receptor, the opioid receptors, are known to couple productively to these G proteins [2].

Analytical, diagnostic and therapeutic context of OPRL1

  • A site-directed mutagenesis approach has been used to gain insight into the molecular events whereby the heptadecapeptide nociceptin binds and activates the opioid receptor-like 1 (ORL1) receptor, a G protein-coupled receptor [18].
  • In addition, we studied the nociceptin receptor at mRNA levels by RT-PCR and the vasomotor response to nociceptin in human cerebral vessels using a sensitive in vitro method [17].
  • Using in situ hybridization techniques, the present study was undertaken to determine the normal pattern of expression of ORL1 mRNA in the human and rat brain at various developmental stages [26].
  • Ovariectomies were performed on female Sprague-Dawley rats, and their plasma luteinizing hormone (LH) levels were measured after icv injection of OFQ with or without [Nphe1]NC(1-13)NH2, a competitive antagonist of opioid receptor-like1 receptor (ORL1 receptor) [27].
  • The tissue distribution of the nORL receptor, as determined by reverse transcriptase PCR, was also found to differ from reports on the mammalian ORL1 receptor, with mRNA detected in brain, spinal cord, and lung, but not detected in a number of other peripheral tissues reported to express the receptor in mammals [28].


  1. Mu-opioid-induced desensitization of opioid receptor-like 1 and mu-opioid receptors: differential intracellular signaling determines receptor sensitivity. Mandyam, C.D., Thakker, D.R., Standifer, K.M. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  2. GalphaL1 (Galpha14) couples the opioid receptor-like1 receptor to stimulation of phospholipase C. Yung, L.Y., Joshi, S.A., Chan, R.Y., Chan, J.S., Pei, G., Wong, Y.H. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  3. Functional expression, activation and desensitization of opioid receptor-like receptor ORL1 in neuroblastoma x glioma NG108-15 hybrid cells. Ma, L., Cheng, Z.J., Fan, G.H., Cai, Y.C., Jiang, L.Z., Pei, G. FEBS Lett. (1997) [Pubmed]
  4. Regulation of proinflammatory cytokines gene expression by nociceptin/orphanin FQ in the spinal cord and the cultured astrocytes. Fu, X., Zhu, Z.H., Wang, Y.Q., Wu, G.C. Neuroscience (2007) [Pubmed]
  5. Metallophthalocyanines photosensitize the breakdown of (hydro)peroxides in solution to yield hydroxyl or alkoxyl and peroxyl free radicals via different interaction pathways. Gantchev, T.G., Sharman, W.M., van Lier, J.E. Photochem. Photobiol. (2003) [Pubmed]
  6. Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: research tools and potential therapeutic agents. Zaveri, N. Life Sci. (2003) [Pubmed]
  7. No association between polymorphisms in the lectin-like oxidised low density lipoprotein receptor (ORL1) gene on chromosome 12 and Alzheimer's disease in a UK cohort. Pritchard, A., St Clair, D., Lemmon, H., Mann, D.M., Lendon, C. Neurosci. Lett. (2004) [Pubmed]
  8. Lack of polymorphism in genes encoding mGluR 7, mGluR 8, GABA(A) receptor alfa-6 subunit and nociceptin/orphanin FQ receptor and panic disorder. Kobayashi, Y., Akiyoshi, J., Kanehisa, M., Ichioka, S., Tanaka, Y., Tsuru, J., Hanada, H., Kodama, K., Isogawa, K., Tsutsumi, T. Psychiatr. Genet. (2007) [Pubmed]
  9. Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Meunier, J.C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J.L., Guillemot, J.C., Ferrara, P., Monsarrat, B. Nature (1995) [Pubmed]
  10. The nociceptin pharmacophore site for opioid receptor binding derived from the NMR structure and bioactivity relationships. Orsini, M.J., Nesmelova, I., Young, H.C., Hargittai, B., Beavers, M.P., Liu, J., Connolly, P.J., Middleton, S.A., Mayo, K.H. J. Biol. Chem. (2005) [Pubmed]
  11. Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4. Serhan, C.N., Fierro, I.M., Chiang, N., Pouliot, M. J. Immunol. (2001) [Pubmed]
  12. Direct identification of a peptide binding region in the opioid receptor-like 1 receptor by photoaffinity labeling with [Bpa(10),Tyr(14)]nociceptin. Moulédous, L., Topham, C.M., Mazarguil, H., Meunier, J.C. J. Biol. Chem. (2000) [Pubmed]
  13. A core-promoter region functions bi-directionally for human opioid-receptor-like gene ORL1 and its 5'-adjacent gene GAIP. Ito, E., Xie, G., Maruyama, K., Palmer, P.P. J. Mol. Biol. (2000) [Pubmed]
  14. Ligand-regulated internalization of the opioid receptor-like 1: a confocal study. Corbani, M., Gonindard, C., Meunier, J.C. Endocrinology (2004) [Pubmed]
  15. Agonist-induced internalization and desensitization of the human nociceptin receptor expressed in CHO cells. Spampinato, S., Di Toro, R., Alessandri, M., Murari, G. Cell. Mol. Life Sci. (2002) [Pubmed]
  16. Induction of G protein-coupled receptor kinases 2 and 3 contributes to the cross-talk between mu and ORL1 receptors following prolonged agonist exposure. Thakker, D.R., Standifer, K.M. Neuropharmacology (2002) [Pubmed]
  17. Nociceptin immunoreactivity and receptor mRNA in the human trigeminal ganglion. Hou, M., Uddman, R., Tajti, J., Edvinsson, L. Brain Res. (2003) [Pubmed]
  18. 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. Mouledous, L., Topham, C.M., Moisand, C., Mollereau, C., Meunier, J.C. Mol. Pharmacol. (2000) [Pubmed]
  19. Agonistic effect of buprenorphine in a nociceptin/OFQ receptor-triggered reporter gene assay. Wnendt, S., Krüger, T., Janocha, E., Hildebrandt, D., Englberger, W. Mol. Pharmacol. (1999) [Pubmed]
  20. N-terminal modifications leading to peptide ORL1 partial agonists and antagonists. Judd, A.K., Kaushanskaya, A., Tuttle, D.J., Sanchez, A., Khroyan, T., Polgar, W., Toll, L. J. Pept. Res. (2003) [Pubmed]
  21. Biostable aptamers with antagonistic properties to the neuropeptide nociceptin/orphanin FQ. Faulhammer, D., Eschgfäller, B., Stark, S., Burgstaller, P., Englberger, W., Erfurth, J., Kleinjung, F., Rupp, J., Dan Vulcu, S., Schröder, W., Vonhoff, S., Nawrath, H., Gillen, C., Klussmann, S. RNA (2004) [Pubmed]
  22. 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. Mandyam, C.D., Thakker, D.R., Christensen, J.L., Standifer, K.M. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
  23. Cellular actions of nociceptin: transduction mechanisms. Hawes, B.E., Graziano, M.P., Lambert, D.G. Peptides (2000) [Pubmed]
  24. Characterisation of the non-peptide nociceptin receptor agonist, Ro64-6198 in Chinese hamster ovary cells expressing recombinant human nociceptin receptors. Hashiba, E., Lambert, D.G., Jenck, F., Wichmann, J., Smith, G. Life Sci. (2002) [Pubmed]
  25. Orphanin FQ/nociceptin blocks chronic morphine-induced tyrosine hydroxylase upregulation. Thakker, D.R., Standifer, K.M. Brain Res. Mol. Brain Res. (2002) [Pubmed]
  26. Expression of orphanin FQ and the opioid receptor-like (ORL1) receptor in the developing human and rat brain. Neal, C.R., Akil, H., Watson, S.J. J. Chem. Neuroanat. (2001) [Pubmed]
  27. Involvement of nociceptin/orphanin FQ in release of hypothalamic GnRH mediated by ORL1 receptor in ovariectomized rats. An, X.F., Chen, H.P., Ma, S.L., Feng, Y., Hao, J.W., Chen, B.Y. Acta Pharmacol. Sin. (2005) [Pubmed]
  28. Cloning, pharmacological characterization and tissue distribution of an ORL1 opioid receptor from an amphibian, the rough-skinned newt Taricha granulosa. Walthers, E.A., Bradford, C.S., Moore, F.L. J. Mol. Endocrinol. (2005) [Pubmed]
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