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Gene Review

Oprl1  -  opioid receptor-like 1

Mus musculus

Synonyms: K3 opiate receptor, KOR-3, KOR3, Kappa-type 3 opioid receptor, LC132, ...
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Disease relevance of Oprl1

  • Administered nociceptin produces hyperalgesia and hypolocomotion, whereas the nociceptin receptor-knockout mice show no significant abnormalities in nociceptive thresholds and locomotion [1].
  • Nociceptin/orphanin (Noc/oFQ), endogenous agonist for nociceptin receptor (NOR), is thought to be a stimulator of neurogenic inflammation [2].
  • In the present study, we identified the expression of the ORL1 receptor in murine N1E-115 neuroblastoma cells and used this neuronal system to investigate the pharmacological activity of Phe(phi)noc [3].
  • These results indicate that the nociceptin receptor is coupled to the N-type Ca2+ channel via pertussis toxin-sensitive G proteins in NG108-15 cells and that this coupling is associated with rapid and homologous desensitization [4].

Psychiatry related information on Oprl1

  • In addition, the antagonists for the nociceptin receptor may be worth testing for alleviating memory disorders [5].
  • 1. The ORL1 agonists nociceptin and Ro 64-6198 were compared in their ability to modify spontaneous locomotor activity in male NMRI mice not habituated to the test environment [6].
  • ORL-1 agonists have been proposed as potential therapeutics for substance abuse based on their propensity to counter the effects of mu opioid agonists in several systems, and to inhibit mesolimbic dopamine release, while mostly being devoid of aversive properties [7].
  • Here we report the involvement of nociceptin receptor in tolerance to morphine-induced antinociception and in morphine dependence [8].

High impact information on Oprl1

  • Histological analysis revealed the expression of both the nociceptin precursor and the nociceptin receptor in the hippocampus, thought to take part in aspects of learning and memory [9].
  • Although nocistatin does not bind to the nociceptin receptor, it binds to the membrane of mouse brain and of spinal cord with high affinity [10].
  • These results show that the loss of the nociceptin receptor results in a gain-of-function mutation in both the memory process and the long-term potentiation mechanism in CA1, perhaps as a result of altered intracellular signal transduction systems in neurons [9].
  • The nociceptin receptor uses guanine-nucleotide-binding proteins to mediate the inhibition of adenylyl cyclase, the activation of potassium channels and inhibition of calcium channels [9].
  • Together, these findings show that endogenous or exogenous stimulation of the ORL1 receptor can be neurotoxic and that blocking NC signaling protects the white matter against excitotoxic challenge [11].

Biological context of Oprl1


Anatomical context of Oprl1


Associations of Oprl1 with chemical compounds

  • The present results suggest that the activation of the ORL-1 receptor by nociceptin may induce the disinhibition of histaminergic neuron and enhance the release of histamine, which subsequently acts on the H1 receptor located on the SP-containing neurons to produce the spinal cord-mediated nociceptive response [18].
  • These results confirm that the suppressive action of nociceptin on mesolimbic dopamine release is mediated entirely by the ORL1 receptor, and that UFP-101 effectively antagonizes this action [17].
  • All neurons in both the wild-type and micro -receptor-deleted mice responded with similar outward currents to either the GABA(B) receptor agonist baclofen (10 micro M), or the opioid-like receptor ORL1 (NOP) agonist nociceptin (300 nM) [19].
  • ORL1, mu-, delta- and kappa-receptors were labelled with [(3)H] leucyl-nociceptin (0.4 nM), [(3)H] DAMGO (4 nM), [(3)H] deltorphin-I (7 nM), and [(3)H] CI-977 (2.5 nM) respectively [20].
  • Enhanced hippocampal acetylcholine release in nociceptin-receptor knockout mice [21].

Other interactions of Oprl1


Analytical, diagnostic and therapeutic context of Oprl1

  • Although we do not fully understand the mechanisms that produce the difference between the effect of i.c.v. injection of nociceptin/orphanin FQ and that of intrathecal injection of nociceptin/orphanin FQ, we believe that spinal ORL1 receptor may be the next receptor which should be targeted by drugs designed for the treatment of pain [26].
  • The three opioid receptors are known to play central roles in mediating analgesia and many other physiological activities; however, the nociceptin receptor was identified recently and less is known about its physiological roles [27].
  • To determine if the behavioural phenotype of nociceptin/orphanin FQ knockout mice reflects changes in either opioid receptor-like 1 or classical opioid receptor expression, we have carried out quantitative autoradiography of the opioid receptor-like 1, mu-, delta- and kappa-opioid receptors in the brains of these animals [13].
  • The PCR results demonstrate that the region of the mu opioid receptor gene between the first intracellular loop and the third transmembrane domain (TM3) has been highly conserved during evolution and that mu opioid receptor-like sequences are present in the earliest stages of vertebrate evolution [28].
  • Identification of the G-protein-coupled ORL1 receptor in the mouse spinal cord by [35S]-GTPgammaS binding and immunohistochemistry [29].


  1. Loss of antinociception induced by naloxone benzoylhydrazone in nociceptin receptor-knockout mice. Noda, Y., Mamiya, T., Nabeshima, T., Nishi, M., Higashioka, M., Takeshima, H. J. Biol. Chem. (1998) [Pubmed]
  2. Role of nociceptin/orphanin FQ (Noc/oFQ) in murine experimental colitis. Kato, S., Tsuzuki, Y., Hokari, R., Okada, Y., Miyazaki, J., Matsuzaki, K., Iwai, A., Kawaguchi, A., Nagao, S., Itoh, K., Suzuki, H., Nabeshima, T., Miura, S. J. Neuroimmunol. (2005) [Pubmed]
  3. [Phe1phi(CH2-NH)Gly2]nociceptin-(1-13)-NH2 acts as a partial agonist at ORL1 receptor endogenously expressed in mouse N1E-115 neuroblastoma cells. Olianas, M.C., Maullu, C., Ingianni, A., Onali, P. Neuroreport (1999) [Pubmed]
  4. Nociceptin receptor-mediated Ca2+ channel inhibition and its desensitization in NG108-15 cells. Morikawa, H., Fukuda, K., Mima, H., Shoda, T., Kato, S., Mori, K. Eur. J. Pharmacol. (1998) [Pubmed]
  5. The role of nociceptin in cognition. Nabeshima, T., Noda, Y., Mamiya, T. Brain Res. (1999) [Pubmed]
  6. Evidence in locomotion test for the functional heterogeneity of ORL-1 receptors. Kuzmin, A., Sandin, J., Terenius, L., Ogren, S.O. Br. J. Pharmacol. (2004) [Pubmed]
  7. The effect of a systemically active ORL-1 agonist, Ro 64-6198, on the acquisition, expression, extinction, and reinstatement of morphine conditioned place preference. Shoblock, J.R., Wichmann, J., Maidment, N.T. Neuropharmacology (2005) [Pubmed]
  8. Morphine tolerance and dependence in the nociceptin receptor knockout mice. Mamiya, T., Noda, Y., Ren, X., Nagai, T., Takeshima, H., Ukai, M., Nabeshima, T. Journal of neural transmission (Vienna, Austria : 1996) (2001) [Pubmed]
  9. Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors. Manabe, T., Noda, Y., Mamiya, T., Katagiri, H., Houtani, T., Nishi, M., Noda, T., Takahashi, T., Sugimoto, T., Nabeshima, T., Takeshima, H. Nature (1998) [Pubmed]
  10. Nocistatin, a peptide that blocks nociceptin action in pain transmission. Okuda-Ashitaka, E., Minami, T., Tachibana, S., Yoshihara, Y., Nishiuchi, Y., Kimura, T., Ito, S. Nature (1998) [Pubmed]
  11. Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain. Laudenbach, V., Calo, G., Guerrini, R., Lamboley, G., Benoist, J.F., Evrard, P., Gressens, P. J. Clin. Invest. (2001) [Pubmed]
  12. Neuronal mechanism of nociceptin-induced modulation of learning and memory: involvement of N-methyl-D-aspartate receptors. Mamiya, T., Yamada, K., Miyamoto, Y., König, N., Watanabe, Y., Noda, Y., Nabeshima, T. Mol. Psychiatry (2003) [Pubmed]
  13. Nociceptin/orphanin FQ knockout mice display up-regulation of the opioid receptor-like 1 receptor and alterations in opioid receptor expression in the brain. Clarke, S., Chen, Z., Hsu, M.S., Hill, R.G., Pintar, J.E., Kitchen, I. Neuroscience (2003) [Pubmed]
  14. Structure and characterization of the gene encoding a mouse kappa3-related opioid receptor. Pan, Y.X., Xu, J., Pasternak, G.W. Gene (1996) [Pubmed]
  15. Distribution of the nociceptin and nocistatin precursor transcript in the mouse central nervous system. Boom, A., Mollereau, C., Meunier, J.C., Vassart, G., Parmentier, M., Vanderhaeghen, J.J., Schiffmann, S.N. Neuroscience (1999) [Pubmed]
  16. Intradermal nociceptin elicits itch-associated responses through leukotriene B(4) in mice. Andoh, T., Yageta, Y., Takeshima, H., Kuraishi, Y. J. Invest. Dermatol. (2004) [Pubmed]
  17. Exogenous, but not endogenous nociceptin modulates mesolimbic dopamine release in mice. Koizumi, M., Midorikawa, N., Takeshima, H., Murphy, N.P. J. Neurochem. (2004) [Pubmed]
  18. Involvement of the histaminergic system in the nociceptin-induced pain-related behaviors in the mouse spinal cord. Sakurada, S., Watanabe, H., Mizoguchi, H., Yonezawa, A., Orito, T., Katsuyama, S., Kuramasu, A., Sakurada, C., Yanai, K., Sakurada, T. Pain (2004) [Pubmed]
  19. Cellular actions of opioids on periaqueductal grey neurons from C57B16/J mice and mutant mice lacking MOR-1. Vaughan, C.W., Bagley, E.E., Drew, G.M., Schuller, A., Pintar, J.E., Hack, S.P., Christie, M.J. Br. J. Pharmacol. (2003) [Pubmed]
  20. Quantitative autoradiographic mapping of the ORL1, mu-, delta- and kappa-receptors in the brains of knockout mice lacking the ORL1 receptor gene. Clarke, S., Chen, Z., Hsu, M.S., Pintar, J., Hill, R., Kitchen, I. Brain Res. (2001) [Pubmed]
  21. Enhanced hippocampal acetylcholine release in nociceptin-receptor knockout mice. Uezu, K., Sano, A., Sei, H., Toida, K., Houtani, T., Sugimoto, T., Suzuki-Yamamoto, T., Takeshima, H., Ishimura, K., Morita, Y. Brain Res. (2005) [Pubmed]
  22. N-terminally truncated variant of the mouse GAIP/RGS19 lacks selectivity of full-length GAIP/RGS19 protein in regulating ORL1 receptor signaling. Xie, G.X., Yanagisawa, Y., Ito, E., Maruyama, K., Han, X., Kim, K.J., Han, K.R., Moriyama, K., Palmer, P.P. J. Mol. Biol. (2005) [Pubmed]
  23. Dissociation of affinity and efficacy in KOR-3 chimeras. Pan, Y.X., Xu, J., Ryan-Moro, J., Mathis, J., Hom, J.S., Mei, J., Pasternak, G.W. FEBS Lett. (1996) [Pubmed]
  24. Cloning and functional characterization through antisense mapping of a kappa 3-related opioid receptor. Pan, Y.X., Cheng, J., Xu, J., Rossi, G., Jacobson, E., Ryan-Moro, J., Brooks, A.I., Dean, G.E., Standifer, K.M., Pasternak, G.W. Mol. Pharmacol. (1995) [Pubmed]
  25. Defective place cell activity in nociceptin receptor knockout mice with elevated NMDA receptor-dependent long-term potentiation. Taverna, F.A., Georgiou, J., McDonald, R.J., Hong, N.S., Kraev, A., Salter, M.W., Takeshima, H., Muller, R.U., Roder, J.C. J. Physiol. (Lond.) (2005) [Pubmed]
  26. Nociceptin/orphanin FQ: role in nociceptive information processing. Yamamoto, T., Nozaki-Taguchi, N., Sakashita, Y., Kimura, S. Prog. Neurobiol. (1999) [Pubmed]
  27. Unrestrained nociceptive response and disregulation of hearing ability in mice lacking the nociceptin/orphaninFQ receptor. Nishi, M., Houtani, T., Noda, Y., Mamiya, T., Sato, K., Doi, T., Kuno, J., Takeshima, H., Nukada, T., Nabeshima, T., Yamashita, T., Noda, T., Sugimoto, T. EMBO J. (1997) [Pubmed]
  28. Mu opioid receptor-like sequences are present throughout vertebrate evolution. Li, X., Keith, D.E., Evans, C.J. J. Mol. Evol. (1996) [Pubmed]
  29. Identification of the G-protein-coupled ORL1 receptor in the mouse spinal cord by [35S]-GTPgammaS binding and immunohistochemistry. Narita, M., Mizoguchi, H., Oji, D.E., Dun, N.J., Hwang, B.H., Nagase, H., Tseng, L.F. Br. J. Pharmacol. (1999) [Pubmed]
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