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Gene Review

OPRK1  -  opioid receptor, kappa 1

Homo sapiens

Synonyms: K-OR-1, KOR, KOR-1, Kappa-type opioid receptor, OPRK
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Disease relevance of OPRK1

  • We report herein the presence of kappa opioid receptors (KORs) in human fetal microglia and inhibition of HIV-1 expression in acutely infected microglial cell cultures treated with KOR ligands [1].
  • This mechanism-based finding provides functional evidence in support of the clinical potential of KOR agonists as antipruritics in the presence of MOR agonist-induced pruritus [2].
  • To achieve a high density of receptors, replication-defective adenovirus (rAd5) vectors encoding the mu (MOR) and kappa (KOR) opioid receptors, both in their native form and as fusion proteins bearing the green fluorescent protein (GFP) at their C-terminus, were constructed [3].
  • CONCLUSIONS/INTERPRETATION: Using selective peripheral KOR agonists to take advantage of elevated peripheral KOR expression may provide a novel therapeutic approach for painful diabetic neuropathy [4].
  • Exploiting the presence and elevated levels of KOR in the periphery, we investigated the effect of the peripheral KOR agonist asimadoline on formalin-evoked hyperalgesia and tactile allodynia in diabetic rats [4].

Psychiatry related information on OPRK1

  • Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction [5].
  • This study: (i) characterized the genomic structure of the hOPRK1 gene; (ii) identified single nucleotide polymorphisms (SNPs) in the hOPRK1 gene; and (iii) investigated possible associations of these variants with vulnerability to develop heroin addiction [5].
  • BACKGROUND: Nonselective opioid antagonists reduce alcohol consumption under various experimental situations, and several association studies have examined possible roles of opioid receptor mu (OPRM), delta (OPRD), and kappa (OPRK) genes in the development of alcohol dependence [6].
  • Based on the selectivity of salvinorin A for the KOR, this receptor represents a potential molecular target for the development of drugs to treat disorders characterized by alterations in perception, including schizophrenia, Alzheimer's disease and bipolar disorder [7].
  • BACKGROUND: Compelling evidence indicates that kappa opioid receptor (KOR) agonists produce perceptual distortions in animals and humans, yet the mechanism of action and clinical relevance of such effects remain unclear [8].

High impact information on OPRK1

  • This study provided evidence for mRNA transport and regulation of presynaptic protein synthesis of nonstructural proteins like KOR in primary sensory neurons and demonstrated a mechanism of KCl depolarization-stimulated axonal mRNA redistribution for localized translational regulation [9].
  • Using reverse transcriptase-polymerase chain reaction and sequencing analyses, we found that mRNA for the KOR was constitutively expressed in microglia and determined that the nucleotide sequence of the open reading frame was identical to that of the human brain KOR gene [1].
  • Significantly, and in agreement with our in silico predictions, substituted cysteine accessibility method analysis of helix 2 comparing KOR and the delta-opioid receptor, which has negligible affinity for salvinorin A, revealed that residues known to be important for salvinorin A binding exhibit a differential pattern of water accessibility [10].
  • When expressed in Chinese hamster ovary (CHO) cells, GEC1 co-immunoprecipitated with FLAG-hKOR [11].
  • TNFalpha and IL-1beta both suppressed the expression of DOR and KOR mRNA in both OA and RA FLS [12].

Chemical compound and disease context of OPRK1

  • Results of flow cytometry studies suggested that the mechanism whereby KOR ligands inhibit cocaine's stimulatory effect on viral expression involves the suppression of cocaine-induced activation of extracellular signal-regulated kinase1/2, thereby blunting cocaine-enhanced up-regulation of the HIV-1 entry chemokine coreceptor CCR5 [13].
  • The kappa opioid receptor (KOR) agonist U50,488 recently has been shown to inhibit HIV-1 p24 antigen production in acutely infected microglial cell cultures [14].

Biological context of OPRK1

  • Family-based analyses demonstrated associations between alcohol dependence and multiple SNPs in the promoter and 3' end of PDYN, and in intron 2 of OPRK1 [15].
  • To define the effects of phosphorylation of this residue in desensitization and internalization processes in mammalian expression systems, wild-type KOR-green fluorescent protein (KOR-GFP) and KOR(S369A)-GFP were stably expressed in AtT-20 and HEK293 cells [16].
  • Direct sequencing of amplified DNA containing all four exons and intron 1 of the hOPRK1 gene were evaluated for polymorphisms in 291 subjects (145 former heroin addicts and 146 controls) [5].
  • Most interestingly, the KOR agonist U69593 may exert an antiarthritic effect via up-regulation of KOR in OA and RA FLS [12].
  • Following 4-h incubation, all three compounds induced down-regulation of the human KOR, with salvinorin A causing a lower extent of down-regulation [17].

Anatomical context of OPRK1

  • These findings suggest that the dysfunction of MOR, but not DOR and KOR, linked to cPKC activation in the spinal cord may be, at least in part, involved in the reduced sensitivity to antinociception induced by morphine under the ethanol-dependent neuropathic pain-like state [18].
  • In the present study, the relative distribution of each type of opioid receptor, mu (MOR), delta (DOR) and kappa (KOR) within GABAergic neurons in the inferior colliculus was examined [19].
  • Using heterologous expression in Xenopus laevis oocytes, we compared the potencies of morphine, morphine-6beta-glucuronide (M6G), and morphine-3-glucuronide (M3G) for cloned human mu- (hMOR), kappa- (hKOR), and delta-opioid receptors (hDOR) [20].
  • Using immunofluorescence, both DOR and KOR proteins were expressed predominantly on the cell membrane with minor staining in the cytoplasm [21].
  • Skin fibroblasts in culture expressed DOR and KOR mRNA [21].

Associations of OPRK1 with chemical compounds

  • Opioid Receptor Gene (OPRM1, OPRK1, and OPRD1) Variants and Response to Naltrexone Treatment for Alcohol Dependence: Results From the VA Cooperative Study [22].
  • These results demonstrate that GRK-mediated phosphorylation of serine 369 mediates rat KOR desensitization and internalization [16].
  • The kappa opioid receptor (KOR) plays a role in stress responsivity, opiate withdrawal and responses to cocaine [5].
  • In contrast, the prototypical nitrogenous KOR agonist U69593 and the endogenous peptidergic agonist dynorphin A (1-13) showed differential requirements for these three residues for binding and activation [23].
  • KOR activation by its endogenous ligand dynorphin A(1-17) decreases basal and drug-induced striatal levels of dopamine [5].

Physical interactions of OPRK1

  • Thus, NHERF-1/EBP50 binds directly to KOR, and this association plays an important role in accelerating Na(+)/H(+) exchange [24].

Regulatory relationships of OPRK1

  • The kappa-agonist U50,488H induced a modest inositol phosphate formation when KOR was expressed alone or with MOR, but the response was attenuated when co-expressing with either DOR or ORL(1) [25].

Other interactions of OPRK1

  • To investigate the possibility that dynorphin A may serve as an agonist for other opioid receptors, we took the advantage of the cloning of the three major types of opioid receptors, mu (MOR), delta (DOR) and KOR, and examined their affinity for and their activation by dynorphin A [26].
  • Expression of GEC1 greatly increased total and cell-surface KOR but not mu or delta opioid receptors [11].
  • The trans-(3,4)-dimethyl-4-(3-hydroxyphenyl)piperidines are a unique class of opioid antagonists that have recently provided selective antagonists for mu-opioid receptors (MOR) and kappa-opioid receptors (KOR) [27].

Analytical, diagnostic and therapeutic context of OPRK1


  1. kappa opioid receptors in human microglia downregulate human immunodeficiency virus 1 expression. Chao, C.C., Gekker, G., Hu, S., Sheng, W.S., Shark, K.B., Bu, D.F., Archer, S., Bidlack, J.M., Peterson, P.K. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  2. Activation of kappa-opioid receptors inhibits pruritus evoked by subcutaneous or intrathecal administration of morphine in monkeys. Ko, M.C., Lee, H., Song, M.S., Sobczyk-Kojiro, K., Mosberg, H.I., Kishioka, S., Woods, J.H., Naughton, N.N. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  3. Transient overexpression of kappa and mu opioid receptors using recombinant adenovirus vectors. Zhen, Z., Bradel-Tretheway, B.G., Dewhurst, S., Bidlack, J.M. J. Neurosci. Methods (2004) [Pubmed]
  4. Dynorphin A, kappa opioid receptors and the antinociceptive efficacy of asimadoline in streptozotocin-induced diabetic rats. Jolivalt, C.G., Jiang, Y., Freshwater, J.D., Bartoszyk, G.D., Calcutt, N.A. Diabetologia (2006) [Pubmed]
  5. Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction. Yuferov, V., Fussell, D., LaForge, K.S., Nielsen, D.A., Gordon, D., Ho, A., Leal, S.M., Ott, J., Kreek, M.J. Pharmacogenetics (2004) [Pubmed]
  6. Endogenous opioid receptor genes and alcohol dependence among Taiwanese Han. Loh, e.l. .W., Fann, C.S., Chang, Y.T., Chang, C.J., Cheng, A.T. Alcohol. Clin. Exp. Res. (2004) [Pubmed]
  7. Salvinorin A: the "magic mint" hallucinogen finds a molecular target in the kappa opioid receptor. Sheffler, D.J., Roth, B.L. Trends Pharmacol. Sci. (2003) [Pubmed]
  8. Kappa opioid receptor activation disrupts prepulse inhibition of the acoustic startle in rats. Bortolato, M., Aru, G.N., Frau, R., Orrù, M., Fà, M., Manunta, M., Puddu, M., Mereu, G., Gessa, G.L. Biol. Psychiatry (2005) [Pubmed]
  9. Axonal mRNA transport and localized translational regulation of {kappa}-opioid receptor in primary neurons of dorsal root ganglia. Bi, J., Tsai, N.P., Lin, Y.P., Loh, H.H., Wei, L.N. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. Differential Helical Orientations among Related G Protein-coupled Receptors Provide a Novel Mechanism for Selectivity: STUDIES WITH SALVINORIN A AND THE {kappa}-OPIOID RECEPTOR. Vortherms, T.A., Mosier, P.D., Westkaemper, R.B., Roth, B.L. J. Biol. Chem. (2007) [Pubmed]
  11. GEC1 interacts with the kappa opioid receptor and enhances expression of the receptor. Chen, C., Li, J.G., Chen, Y., Huang, P., Wang, Y., Liu-Chen, L.Y. J. Biol. Chem. (2006) [Pubmed]
  12. Kappa and delta opioid receptors are expressed but down-regulated in fibroblast-like synoviocytes of patients with rheumatoid arthritis and osteoarthritis. Shen, H., Aeschlimann, A., Reisch, N., Gay, R.E., Simmen, B.R., Michel, B.A., Gay, S., Sprott, H. Arthritis Rheum. (2005) [Pubmed]
  13. Kappa-opioid receptor ligands inhibit cocaine-induced HIV-1 expression in microglial cells. Gekker, G., Hu, S., Wentland, M.P., Bidlack, J.M., Lokensgard, J.R., Peterson, P.K. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  14. U50,488 protection against HIV-1-related neurotoxicity: involvement of quinolinic acid suppression. Chao, C.C., Hu, S., Gekker, G., Lokensgard, J.R., Heyes, M.P., Peterson, P.K. Neuropharmacology (2000) [Pubmed]
  15. Association of the kappa-opioid system with alcohol dependence. Xuei, X., Dick, D., Flury-Wetherill, L., Tian, H.J., Agrawal, A., Bierut, L., Goate, A., Bucholz, K., Schuckit, M., Nurnberger, J., Tischfield, J., Kuperman, S., Porjesz, B., Begleiter, H., Foroud, T., Edenberg, H.J. Mol. Psychiatry (2006) [Pubmed]
  16. Phosphorylation of a carboxyl-terminal serine within the kappa-opioid receptor produces desensitization and internalization. McLaughlin, J.P., Xu, M., Mackie, K., Chavkin, C. J. Biol. Chem. (2003) [Pubmed]
  17. Comparison of pharmacological activities of three distinct kappa ligands (Salvinorin A, TRK-820 and 3FLB) on kappa opioid receptors in vitro and their antipruritic and antinociceptive activities in vivo. Wang, Y., Tang, K., Inan, S., Siebert, D., Holzgrabe, U., Lee, D.Y., Huang, P., Li, J.G., Cowan, A., Liu-Chen, L.Y. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  18. Functional reduction in mu-opioidergic system in the spinal cord under a neuropathic pain-like state following chronic ethanol consumption in the rat. Narita, M., Miyoshi, K., Narita, M., Suzuki, T. Neuroscience (2007) [Pubmed]
  19. Relationship of opioid receptors with GABAergic neurons in the rat inferior colliculus. Tongjaroenbuangam, W., Jongkamonwiwat, N., Phansuwan-Pujito, P., Casalotti, S.O., Forge, A., Dodson, H., Govitrapong, P. Eur. J. Neurosci. (2006) [Pubmed]
  20. Morphine-6beta-glucuronide and morphine-3-glucuronide, opioid receptor agonists with different potencies. Ulens, C., Baker, L., Ratka, A., Waumans, D., Tytgat, J. Biochem. Pharmacol. (2001) [Pubmed]
  21. Detection of kappa and delta opioid receptors in skin--outside the nervous system. Salemi, S., Aeschlimann, A., Reisch, N., Jüngel, A., Gay, R.E., Heppner, F.L., Michel, B.A., Gay, S., Sprott, H. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  22. Opioid Receptor Gene (OPRM1, OPRK1, and OPRD1) Variants and Response to Naltrexone Treatment for Alcohol Dependence: Results From the VA Cooperative Study. Gelernter, J., Gueorguieva, R., Kranzler, H.R., Zhang, H., Cramer, J., Rosenheck, R., Krystal, J.H. Alcohol. Clin. Exp. Res. (2007) [Pubmed]
  23. Identification of the molecular mechanisms by which the diterpenoid salvinorin A binds to kappa-opioid receptors. Yan, F., Mosier, P.D., Westkaemper, R.B., Stewart, J., Zjawiony, J.K., Vortherms, T.A., Sheffler, D.J., Roth, B.L. Biochemistry (2005) [Pubmed]
  24. kappa Opioid receptor interacts with Na(+)/H(+)-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) to stimulate Na(+)/H(+) exchange independent of G(i)/G(o) proteins. Huang, P., Steplock, D., Weinman, E.J., Hall, R.A., Ding, Z., Li, J., Wang, Y., Liu-Chen, L.Y. J. Biol. Chem. (2004) [Pubmed]
  25. Co-expressions of different opioid receptor types differentially modulate their signaling via G(16). Ho, M.K., New, D.C., Wong, Y.H. Neurosignals (2002) [Pubmed]
  26. Dynorphin A as a potential endogenous ligand for four members of the opioid receptor gene family. Zhang, S., Tong, Y., Tian, M., Dehaven, R.N., Cortesburgos, L., Mansson, E., Simonin, F., Kieffer, B., Yu, L. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  27. Identification of a new scaffold for opioid receptor antagonism based on the 2-amino-1,1-dimethyl-7-hydroxytetralin pharmacophore. Grundt, P., Williams, I.A., Lewis, J.W., Husbands, S.M. J. Med. Chem. (2004) [Pubmed]
  28. Engineering and functional immobilization of opioid receptors. Ott, D., Neldner, Y., Cèbe, R., Dodevski, I., Plückthun, A. Protein Eng. Des. Sel. (2005) [Pubmed]
  29. The kappa opioid receptor is associated with the perception of visceral pain. Black, D., Trevethick, M. Gut (1998) [Pubmed]
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