Kappa Opioid receptor

The κ-Opioid receptor is a type of opioid receptor which binds the peptide opioid dynorphin as the primary endogenous ligand.cite journal | author = James IF, Chavkin C, Goldstein A | title = Selectivity of dynorphin for kappa opioid receptors | journal = Life Sci. | volume = 31 | issue = 12-13 | pages = 1331–4 | year = 1982 | pmid = 6128656 | doi = | url = | issn = ] κ receptors are widely distributed in the brain, spinal cord, and in pain neurons.cite journal | author = Mansour A, Fox CA, Akil H, Watson SJ | title = Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications | journal = Trends Neurosci. | volume = 18 | issue = 1 | pages = 22–9 | year = 1995 | month = January | pmid = 7535487 | doi = | url = http://linkinghub.elsevier.com/retrieve/pii/016622369593946U | issn = ]

Receptor subtypes

Based on receptor binding studies, three variants of the κ-opioid receptor designated κ₁, κ₂, and κ₃ have been characterized.cite journal | author = de Costa BR, Rothman RB, Bykov V, Jacobson AE, Rice KC | title = 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 | journal = J. Med. Chem. | volume = 32 | issue = 2 | pages = 281–3 | year = 1989 | month = February | pmid = 2536435 | doi = | url = | issn = ] cite journal | author = Rothman RB, France CP, Bykov V, De Costa BR, Jacobson AE, Woods JH, Rice KC | title = Pharmacological activities of optically pure enantiomers of the kappa opioid agonist, U50,488, and its cis diastereomer: evidence for three kappa receptor subtypes | journal = Eur. J. Pharmacol. | volume = 167 | issue = 3 | pages = 345–53 | year = 1989 | month = August | pmid = 2553442 | doi = | url = | issn = ] However only one cDNA clone has been identified,cite journal | author = Mansson E, Bare L, Yang D | title = Isolation of a human kappa opioid receptor cDNA from placenta | journal = Biochem. Biophys. Res. Commun. | volume = 202 | issue = 3 | pages = 1431–7 | year = 1994 | month = August | pmid = 8060324 | doi = 10.1006/bbrc.1994.2091 | url = | issn = ] hence these receptor subtypes likely arise from interaction of one κ-opioid receptor protein with other membrane associated proteins.cite journal | author = Jordan BA, Devi LA | title = G-protein-coupled receptor heterodimerization modulates receptor function | journal = Nature | volume = 399 | issue = 6737 | pages = 697–700 | year = 1999 | month = June | pmid = 10385123 | doi = 10.1038/21441 | url = | issn = ]

ignal transduction

κ-Opioid receptor activation by agonists is coupled to the G protein G_i/G₀, which subsequently increases phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurons.cite journal | author = Lawrence DM, Bidlack JM | title = 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 | journal = J. Pharmacol. Exp. Ther. | volume = 266 | issue = 3 | pages = 1678–83 | year = 1993 | month = September | pmid = 8103800 | doi = | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8103800 | issn = ] cite journal | author = Konkoy CS, Childers SR | title = Relationship between kappa 1 opioid receptor binding and inhibition of adenylyl cyclase in guinea pig brain membranes | journal = Biochem. Pharmacol. | volume = 45 | issue = 1 | pages = 207–16 | year = 1993 | month = January | pmid = 8381004 | doi = | url = http://linkinghub.elsevier.com/retrieve/pii/0006-2952(93)90394-C | issn = ] cite journal | author = Schoffelmeer AN, Rice KC, Jacobson AE, "et al" | title = Mu-, delta- and kappa-opioid receptor-mediated inhibition of neurotransmitter release and adenylate cyclase activity in rat brain slices: studies with fentanyl isothiocyanate | journal = Eur. J. Pharmacol. | volume = 154 | issue = 2 | pages = 169–78 | year = 1988 | month = September | pmid = 2906610 | doi = | url = http://linkinghub.elsevier.com/retrieve/pii/0014-2999(88)90094-5 | issn = ] κ-Opioid receptors also couple to inward-rectifier potassiumcite journal | author = Henry DJ, Grandy DK, Lester HA, Davidson N, Chavkin C | title = Kappa-opioid receptors couple to inwardly rectifying potassium channels when coexpressed by Xenopus oocytes | journal = Mol. Pharmacol. | volume = 47 | issue = 3 | pages = 551–7 | year = 1995 | month = March | pmid = 7700253 | doi = | url = http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7700253 | issn = ] and to N-type calcium ion channels.cite journal | author = Tallent M, Dichter MA, Bell GI, Reisine T | title = The cloned kappa opioid receptor couples to an N-type calcium current in undifferentiated PC-12 cells | journal = Neuroscience | volume = 63 | issue = 4 | pages = 1033–40 | year = 1994 | month = December | pmid = 7700508 | doi = | url = http://linkinghub.elsevier.com/retrieve/pii/0306-4522(94)90570-3 | issn = ]

Ligands

The synthetic alkaloid ketazocinecite journal | author = Pasternak GW | title = Multiple opiate receptors: [3H] ethylketocyclazocine receptor binding and ketocyclazocine analgesia | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 77 | issue = 6 | pages = 3691–4 | year = 1980 | month = June | pmid = 6251477 | doi = | url = | issn = ] and terpenoid natural product salvinorin Acite journal | author = Roth BL, Baner K, Westkaemper R, "et al" | title = Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 18 | pages = 11934–9 | year = 2002 | month = September | pmid = 12192085 | doi = 10.1073/pnas.182234399 | url = | issn = ] 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.cite journal | author = Holtzman SG | title = Drug discrimination studies | journal = Drug Alcohol Depend | volume = 14 | issue = 3-4 | pages = 263–82 | year = 1985 | month = February | pmid = 2859972 | doi = | url = | issn = ]

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:

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.cite journal | author = Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB | title = Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 18 | pages = 11934–9 | year = 2002 | pmid = 12192085 | doi = 10.1073/pnas.182234399 | issn = ]

The involvement of the kappa-opioid receptor in stress response has been elucidated.cite journal | author = Benjamin B. Land, Michael R. Bruchas, Julia C. Lemos, Mei Xu, Erica J. Melief, and Charles Chavkin | title = The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin kappa-Opioid System | journal = J. Neurosci. | volume = 28 | issue = 2 | pages = 407–414 | year = 2008 | pmid = 18184783 | doi = 10.1523| issn = | url = http://www.jneurosci.org/content/vol28/issue2/#BEHAVIORAL_SYSTEMS ]

Activation of the κ-opioid receptor appears to antagonize many of the effects of the μ opioid receptor.cite journal | author = Pan ZZ | title = mu-Opposing actions of the kappa-opioid receptor | journal = Trends Pharmacol. Sci. | volume = 19 | issue = 3 | pages = 94–8 | year = 1998 | pmid = 9584625 | doi = 10.1016/S0165-6147(98)01169-9 | issn = ]

Kappa ligands are also known for their characteristic diuretic effects, due to their negative regulation of antidiuretic hormone (ADH).cite journal | author = Yamada K, Imai M, Yoshida S | title = Mechanism of diuretic action of U-62,066E, a kappa opioid receptor agonist | journal = Eur. J. Pharmacol. | volume = 160 | issue = 2 | pages = 229–37 | year = 1989 | pmid = 2547626 | doi = | issn = ]

Kappa agonism is neuroprotective against hypoxia/ischemia; as such, kappa receptors may represent a novel therapeutic target.cite journal | author = Zeynalov E, Nemoto M, Hurn PD, Koehler RC, Bhardwaj A | title = Neuroprotective effect of selective kappa opioid receptor agonist is gender specific and linked to reduced neuronal nitric oxide | journal = J. Cereb. Blood Flow Metab. | volume = 26 | issue = 3 | pages = 414–20 | year = 2006 | pmid = 16049424 | doi = 10.1038/sj.jcbfm.9600196 | issn = ]

References

External links

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