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- The title of this article should be Kappa Opioid receptor. The initial letter is capitalized due to technical restrictions.
The κ-Opioid receptor is a type of opioid receptor which binds the peptide opioid dynorphin as the primary endogenous ligand. κ receptors are widely distributed in the brain, spinal cord, and in pain neurons.
Based on receptor binding studies, three variants of the κ-opioid receptor designated κ1, κ2, and κ3 have been characterized. However only one cDNA clone has been identified, hence these receptor subtypes likely arise from interaction of one κ-opioid receptor protein with other membrane associated proteins.
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. κ-Opioid receptors also couple to inward-rectifier potassium and to N-type calcium ion channels.
The synthetic alkaloid ketazocine and terpenoid natural product salvinorin A 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.
- Salvinorin A
It has long been understood that kappa-opioid receptor agonists are dysphoric  but dysphoria from kappa opioids has been shown to differ between sexes. More recent studies have shown the aversive properties in a variety of ways and the kappa receptor has been strongly implicated as an integral neurochemical component of addiction and the remission thereof.
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.
Kappa opioids have recently been investigated for their therapeutic potential in the treatment of addiction and evidence points towards dynorphin, the endogenous kappa agonist, to be the body's natural addiction control mechanism. Childhood stress/abuse is a well known predictor of drug abuse and is reflected in alterations of the mu and kappa opioid systems. The area of the brain most strongly associated with addiction is the nucleus accumbens (NAcc) and striatum while some of the surrounding structures also play an important role. Though many other changes occur, most commonly addiction is characterized by the reduction of dopamine D2 receptors in the NAcc. In addition to low NAcc D2 binding,cocaine is also known to produce a variety of changes to the primate brain such as increases prodynorphin mRNA in caudate patumen (striatum) and decreases of the same in the hypothalamus while the administration of a kappa agonist produced an opposite effect thereby causing the "healing" effect of increased D2 receptors in the NAcc.
Additionally, while cocaine overdose victims showed a large increase in kappa receptors (doubled) in the NAcc, kappa opioid agonist administration is shown to be effective in decreasing cocaine seeking and self-administration. Furthermore, while cocaine abuse is associated with lowered prolactin response, kappa opioid activation causes a release in prolactin, a hormone known for its important role in learning, neuronal plasticity and myelination.
Though cocaine abuse is a frequently used model of addiction, kappa opioids have very marked effects on all types of addiction including alcohol and opiate abuse. Not only are genetic differences in dynorphin receptor expression a marker for alchohol dependance, but a single dose of a kappa opioid antagonist markedly increased alcohol consumption in lab animals. There are numerous studies which reflect a reduction in self-administration of alchohol,and heroin dependance has also been shown to be effectively treated with kappa agonism by reducing the immediate rewarding effects and by causing the curative effect of up-regulation of mu-opioid receptors which have been down-regulated during opioid abuse.
The deleterious behavioral effects of addiction may be, in part, through the modulatory role D2 receptors of the NAcc play in acetylcholine release in the prefrontal cortex (PFC). Because D2 agonism negatively modulates acetylcholine function in the PFC, extreme central cholinergic function may result from the lower D2 binding rates found in addiction. High cholinergic function of the PFC is associated with mental disorders such as schizophrenia, and high function of these neurons may result in excitotoxicity in areas important for executive function(long-term goal-oriented behavior).
The anti-addictive properties of kappa opioid agonists are mediated through both long-term and short-term effects. The immediate effect of kappa agonism leads to reduction of dopamine release in the NAcc during self administration of an addictive substance and over the long term up-regulates receptors which have been down-regulated during substance abuse such as mu-opioid and D2 (dopamine) receptors. These receptors modulate the release of other neurochemicals such as serotoninin the case of mu-opioids and acetylcholine in the case of d2. These changes can account for the physical and psychological remission of the pathology of addiction. Additionally, the release of prolactin which is characteristic of kappa agonism may be an integral part of overcoming the psychological and behavioral aspects of addiction.
Cannabis sativa: The active component of cannabis, THC, is a partial kappa-opioid agonist and may account for the aversive affects of "paranoia" experienced during its use as well as the counter-intuitive non-addictive properties of cannabis.
Ibogaine: Used successfully for the treatment of addiction in most developed countries other than the US, ibogaine has become an icon of addiction management but can be dangerous or fatal. Ibogaine is also a kappa opioid agonist and the information surrounding kappa agonism may prove to be a large portion of the drug's efficacy.
- ↑ James IF, Chavkin C, Goldstein A (1982). Selectivity of dynorphin for kappa opioid receptors. Life Sci. 31 (12-13): 1331–4.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Jordan BA, Devi LA (June 1999). G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399 (6737): 697–700.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 13.0 13.1 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.
- ↑ Holtzman SG (February 1985). Drug discrimination studies. Drug Alcohol Depend 14 (3-4): 263–82.
- ↑ 15.0 15.1 The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system.
- ↑ Sex differences in the potency of kappa opioids and mixed-action opioids administered systemically and at the site of inflammation against capsaicin-induced hyperalgesia in rats.
- ↑ Gender differences in kappa-opioid modulation of cocaine-induced behavior and NMDA-evoked dopamine release.
- ↑ 18.0 18.1 Association of the kappa-opioid system with alcohol dependence..
- ↑ Pan ZZ (1998). mu-Opposing actions of the kappa-opioid receptor. Trends Pharmacol. Sci. 19 (3): 94–8.
- ↑ 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.
- ↑ 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.
- ↑ Hasebe K, Kawai K, Suzuki T, Kawamura K, Tanaka T, Narita M, Nagase H, Suzuki T (October 2004). Possible pharmacotherapy of the opioid kappa receptor agonist for drug dependence. Annals of the New York Academy of Sciences 1025: 404–13.
- ↑ Frankel PS, Alburges ME, Bush L, Hanson GR, Kish SJ (July 2008). Striatal and ventral pallidum dynorphin concentrations are markedly increased in human chronic cocaine users. Neuropharmacology 55 (1): 41–6.
- ↑ Michaels CC, Holtzman SG (April 2008). Early postnatal stress alters place conditioning to both mu- and kappa-opioid agonists. The Journal of pharmacology and experimental therapeutics 325 (1): 313–8.
- ↑ Blum K, Braverman ER, Holder JM, Lubar JF, Monastra VJ, Miller D, Lubar JO, Chen TJ, Comings DE (November 2000). Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. Journal of psychoactive drugs 32 Suppl: i–iv, 1–112.
- ↑ Stefański R, Ziółkowska B, Kuśmider M, Mierzejewski P, Wyszogrodzka E, Kołomańska P, Dziedzicka-Wasylewska M, Przewłocki R, Kostowski W (July 2007). Active versus passive cocaine administration: differences in the neuroadaptive changes in the brain dopaminergic system. Brain research 1157: 1–10.
- ↑ Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP (September 1998). Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys. Synapse (New York, N.Y.) 30 (1): 88–96.
- ↑ D'Addario C, Di Benedetto M, Izenwasser S, Candeletti S, Romualdi P (January 2007). Role of serotonin in the regulation of the dynorphinergic system by a kappa-opioid agonist and cocaine treatment in rat CNS. Neuroscience 144 (1): 157–64.
- ↑ Mash DC, Staley JK (June 1999). D3 dopamine and kappa opioid receptor alterations in human brain of cocaine-overdose victims. Annals of the New York Academy of Sciences 877: 507–22.
- ↑ Schenk S, Partridge B, Shippenberg TS (June 1999). U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking. Psychopharmacology 144 (4): 339–46.
- ↑ Patkar AA, Mannelli P, Hill KP, Peindl K, Pae CU, Lee TH (August 2006). Relationship of prolactin response to meta-chlorophenylpiperazine with severity of drug use in cocaine dependence. Human psychopharmacology 21 (6): 367–75.
- ↑ Butelman ER, Kreek MJ (July 2001). kappa-Opioid receptor agonist-induced prolactin release in primates is blocked by dopamine D(2)-like receptor agonists. European journal of pharmacology 423 (2-3): 243–9.
- ↑ Gregg C, Shikar V, Larsen P, Mak G, Chojnacki A, Yong VW, Weiss S (February 2007). White matter plasticity and enhanced remyelination in the maternal CNS. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 (8): 1812–23.
- ↑ Mitchell JM, Liang MT, Fields HL (November 2005). A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats. Psychopharmacology 182 (3): 384–92.
- ↑ Walker BM, Koob GF (February 2008). Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 33 (3): 643–52.
- ↑ Xi ZX, Fuller SA, Stein EA (January 1998). [hthttp://jpet.aspetjournals.org/cgi/content/abstract/284/1/151 Dopamine release in the nucleus accumbens during heroin self-administration is modulated by kappa opioid receptors: an in vivo fast-cyclic voltammetry study]. The Journal of pharmacology and experimental therapeutics 284 (1): 151–61.
- ↑ Narita M, Khotib J, Suzuki M, Ozaki S, Yajima Y, Suzuki T (June 2003). Heterologous mu-opioid receptor adaptation by repeated stimulation of kappa-opioid receptor: up-regulation of G-protein activation and antinociception. Journal of neurochemistry 85 (5): 1171–9.
- ↑ Brooks JM, Sarter M, Bruno JP (September 2007). D2-like receptors in nucleus accumbens negatively modulate acetylcholine release in prefrontal cortex. Neuropharmacology 53 (3): 455–63.
- ↑ Laplante F, Srivastava LK, Quirion R (April 2004). Alterations in dopaminergic modulation of prefrontal cortical acetylcholine release in post-pubertal rats with neonatal ventral hippocampal lesions. Journal of neurochemistry 89 (2): 314–23.
- ↑ Maisonneuve IM, Archer S, Glick SD (November 1994). U50,488, a kappa opioid receptor agonist, attenuates cocaine-induced increases in extracellular dopamine in the nucleus accumbens of rats. Neuroscience letters 181 (1-2): 57–60.
- ↑ Butelman ER, Mandau M, Tidgewell K, Prisinzano TE, Yuferov V, Kreek MJ (January 2007). Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans. The Journal of pharmacology and experimental therapeutics 320 (1): 300–6.
- ↑ Chavkin C, Sud S, Jin W, Stewart J, Zjawiony JK, Siebert DJ, Toth BA, Hufeisen SJ, Roth BL (March 2004). Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. The Journal of pharmacology and experimental therapeutics 308 (3): 1197–203.
- ↑ Smith PB, Welch SP, Martin BR (March 1994). Interactions between delta 9-tetrahydrocannabinol and kappa opioids in mice. The Journal of pharmacology and experimental therapeutics 268 (3): 1381–7.
- ↑ Hampson RE, Mu J, Deadwyler SA (November 2000). Cannabinoid and kappa opioid receptors reduce potassium K current via activation of G(s) proteins in cultured hippocampal neurons. Journal of neurophysiology 84 (5): 2356–64.
- ↑ Glick SD, Maisonneuve IS (May 1998). Mechanisms of antiaddictive actions of ibogaine. Annals of the New York Academy of Sciences 844: 214–26.
- κ opioid receptor. IUPHAR Receptor Database. International Union of Pharmacology. URL accessed on 2008-05-18.
- MeSH kappa+Opioid+Receptor
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