kappa Opioid receptor

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Opioid receptor, kappa 1
Identifiers
Symbol(s) OPRK1; KOR; OPRK
External IDs OMIM: 165196 MGI: 97439 HomoloGene: 20253
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 4986 18387
Ensembl ENSG00000082556 ENSMUSG00000025905
Uniprot P41145 Q14AL5
Refseq NM_000912 (mRNA)
NP_000903 (protein)		 NM_011011 (mRNA)
NP_035141 (protein)
Location Chr 8: 54.3 - 54.33 Mb Chr 1: 5.58 - 5.59 Mb
Pubmed search [1] [2]

The κ-Opioid receptor is a type of opioid receptor which binds the peptide opioid dynorphin as the primary endogenous ligand.[1] κ receptors are widely distributed in the brain, spinal cord, and in pain neurons.[2]

Contents

[edit] Receptor subtypes

Based on receptor binding studies, three variants of the κ-opioid receptor designated κ1, κ2, and κ3 have been characterized.[3][4] However only one cDNA clone has been identified,[5] hence these receptor subtypes likely arise from interaction of one κ-opioid receptor protein with other membrane associated proteins.[6]

[edit] Signal transduction

κ-Opioid receptor activation by agonists is coupled to the G protein Gi/G0, which subsequently increases phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurons.[7][8][9] κ-Opioid receptors also couple to inward-rectifier potassium[10] and to N-type calcium ion channels.[11]

[edit] Ligands

The synthetic alkaloid ketazocine[12] and terpenoid natural product salvinorin A[13] are potent and selective κ-opioid receptor agonists. The κ-opioid receptor also mediates the action of the hallucinogenic side effects of opioids such as pentazocine.[14]

[edit] Function

It has long been believed that kappa-opioid receptor agonists are dysphoric. This misconception traces back to early articles in the 1980s about human tests with κ-opioid receptor agonists. It was stated that:

"Both doses of ketocyclazocine substantially elevated scores on the LSD subscale of the ARCI as did the high dose of cyclazocine (fig. 2C). Morphine failed to increase scores significantly on this scale which measures dysphoria."[15]

It is now widely accepted that κ-opioid receptor (partial) agonists have hallucinogenic ("psychotomimetic") effects, as exemplified by salvinorin A. These effects are generally undesirable in medicinal drugs and could have had frightening or disturbing effects in the tested humans. It is thought that the hallucinogenic effects of drugs such as butorphanol, nalbuphine, and pentazocine serve to limit their opiate abuse potential. In the case of salvinorin A, a structurally novel neoclerodane diterpene κ-opioid receptor agonist, these hallucinogenic effects are sought after. While salvinorin A is considered a hallucinogen, its effects are qualitatively different than those produced by the classical psychedelic hallucinogens such as LSD or mescaline.[13]

The involvement of the kappa-opioid receptor in stress response has been elucidated.[16]

Activation of the κ-opioid receptor appears to antagonize many of the effects of the μ opioid receptor.[17]

Kappa ligands are also known for their characteristic diuretic effects, due to their negative regulation of antidiuretic hormone (ADH).[18]

Kappa agonism is neuroprotective against hypoxia/ischemia; as such, kappa receptors may represent a novel therapeutic target.[19]

[edit] References

  1. ^ James IF, Chavkin C, Goldstein A (1982). "Selectivity of dynorphin for kappa opioid receptors". Life Sci. 31 (12-13): 1331–4. PMID 6128656. 
  2. ^ Mansour A, Fox CA, Akil H, Watson SJ (January 1995). "Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications". Trends Neurosci. 18 (1): 22–9. PMID 7535487. 
  3. ^ de Costa BR, Rothman RB, Bykov V, Jacobson AE, Rice KC (February 1989). "Selective and enantiospecific acylation of kappa opioid receptors by (1S,2S)-trans-2-isothiocyanato-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexy l] benzeneacetamide. Demonstration of kappa receptor heterogeneity". J. Med. Chem. 32 (2): 281–3. PMID 2536435. 
  4. ^ Rothman RB, France CP, Bykov V, De Costa BR, Jacobson AE, Woods JH, Rice KC (August 1989). "Pharmacological activities of optically pure enantiomers of the kappa opioid agonist, U50,488, and its cis diastereomer: evidence for three kappa receptor subtypes". Eur. J. Pharmacol. 167 (3): 345–53. PMID 2553442. 
  5. ^ Mansson E, Bare L, Yang D (August 1994). "Isolation of a human kappa opioid receptor cDNA from placenta". Biochem. Biophys. Res. Commun. 202 (3): 1431–7. doi:10.1006/bbrc.1994.2091. PMID 8060324. 
  6. ^ Jordan BA, Devi LA (June 1999). "G-protein-coupled receptor heterodimerization modulates receptor function". Nature 399 (6737): 697–700. doi:10.1038/21441. PMID 10385123. 
  7. ^ Lawrence DM, Bidlack JM (September 1993). "The kappa opioid receptor expressed on the mouse R1.1 thymoma cell line is coupled to adenylyl cyclase through a pertussis toxin-sensitive guanine nucleotide-binding regulatory protein". J. Pharmacol. Exp. Ther. 266 (3): 1678–83. PMID 8103800. 
  8. ^ Konkoy CS, Childers SR (January 1993). "Relationship between kappa 1 opioid receptor binding and inhibition of adenylyl cyclase in guinea pig brain membranes". Biochem. Pharmacol. 45 (1): 207–16. PMID 8381004. 
  9. ^ Schoffelmeer AN, Rice KC, Jacobson AE, et al (September 1988). "Mu-, delta- and kappa-opioid receptor-mediated inhibition of neurotransmitter release and adenylate cyclase activity in rat brain slices: studies with fentanyl isothiocyanate". Eur. J. Pharmacol. 154 (2): 169–78. PMID 2906610. 
  10. ^ Henry DJ, Grandy DK, Lester HA, Davidson N, Chavkin C (March 1995). "Kappa-opioid receptors couple to inwardly rectifying potassium channels when coexpressed by Xenopus oocytes". Mol. Pharmacol. 47 (3): 551–7. PMID 7700253. 
  11. ^ Tallent M, Dichter MA, Bell GI, Reisine T (December 1994). "The cloned kappa opioid receptor couples to an N-type calcium current in undifferentiated PC-12 cells". Neuroscience 63 (4): 1033–40. PMID 7700508. 
  12. ^ Pasternak GW (June 1980). "Multiple opiate receptors: [3H]ethylketocyclazocine receptor binding and ketocyclazocine analgesia". Proc. Natl. Acad. Sci. U.S.A. 77 (6): 3691–4. PMID 6251477. 
  13. ^ a b Roth BL, Baner K, Westkaemper R, et al (September 2002). "Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist". Proc. Natl. Acad. Sci. U.S.A. 99 (18): 11934–9. doi:10.1073/pnas.182234399. PMID 12192085. 
  14. ^ Holtzman SG (February 1985). "Drug discrimination studies". Drug Alcohol Depend 14 (3-4): 263–82. PMID 2859972. 
  15. ^ Kumor KM, Haertzen CA, Johnson RE, Kocher T, Jasinski D (1986). "Human psychopharmacology of ketocyclazocine as compared with cyclazocine, morphine and placebo". J. Pharmacol. Exp. Ther. 238 (3): 960–8. PMID 3018228. 
  16. ^ Benjamin B. Land, Michael R. Bruchas, Julia C. Lemos, Mei Xu, Erica J. Melief, and Charles Chavkin (2008). "The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin kappa-Opioid System". J. Neurosci. 28 (2): 407–414. doi:10.1523. PMID 18184783. 
  17. ^ Pan ZZ (1998). "mu-Opposing actions of the kappa-opioid receptor". Trends Pharmacol. Sci. 19 (3): 94–8. doi:10.1016/S0165-6147(98)01169-9. PMID 9584625. 
  18. ^ Yamada K, Imai M, Yoshida S (1989). "Mechanism of diuretic action of U-62,066E, a kappa opioid receptor agonist". Eur. J. Pharmacol. 160 (2): 229–37. PMID 2547626. 
  19. ^ Zeynalov E, Nemoto M, Hurn PD, Koehler RC, Bhardwaj A (2006). "Neuroprotective effect of selective kappa opioid receptor agonist is gender specific and linked to reduced neuronal nitric oxide". J. Cereb. Blood Flow Metab. 26 (3): 414–20. doi:10.1038/sj.jcbfm.9600196. PMID 16049424. 

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