|Opioid receptor, kappa 1|
Crystallographic structure of the human κ-opioid receptor homo dimer ( ) imbedded in a cartoon representation of a lipid bilayer. Each monomer is individually rainbow color-ed (N-terminus = blue, C-terminus = red). The receptor is bound to the ligand JDTic.
|Symbols||; KOR; OPRK|
|External IDs||IUPHAR: ChEMBL: GeneCards:|
|RNA expression pattern|
The κ-opioid receptor (KOR) is a protein that in humans is encoded by the OPRK1 gene. The KOR is one of four related receptors that bind opiate-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering the perception of pain, consciousness, motor control, and mood.
The KOR is a type of opioid receptor that binds the opioid peptide dynorphin as the primary endogenous ligand (substrate naturally occurring in the body). In addition to dynorphin, a variety of natural alkaloids and synthetic ligands bind to the receptor. The KOR may provide a natural addiction control mechanism, and therefore, drugs that act as agonists and increase activation of this receptor may have therapeutic potential in the treatment of addiction.
Based on receptor binding studies, three variants of the KOR 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 KOR protein with other membrane associated proteins.
Similarly to μ-opioid receptor (MOR) agonists, KOR agonists are analgesic. However, KOR agonists also produce side effects such as dysphoria and hallucinations, which limits their clinical usefulness.
It has long been understood that KOR agonists are dysphoric. More recent studies have shown the aversive properties in a variety of ways and the KOR has been strongly implicated as an integral neurochemical component of addiction and the remission thereof.
It is now widely accepted that KOR agonists have dissociative and hallucinogenic effects, as exemplified by salvinorin A. These effects are generally undesirable in medicinal drugs. It is thought that the hallucinogenic effects of drugs such as butorphanol, nalbuphine, and pentazocine serve to limit their opioid abuse potential. In the case of salvinorin A, a structurally novel neoclerodane diterpene KOR agonist, these hallucinogenic effects are sought after, even though the experience is often considered dysphoric by the user. 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.
Activation of the KOR appears to antagonize many of the effects of the MOR.
KOR 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. KORs also couple to inward-rectifier potassium and to N-type calcium ion channels. Recent studies have also demonstrated that agonist-induced stimulation of the KOR, like other G-protein coupled receptors, can result in the activation of mitogen-activated protein kinases (MAPK). These include extracellular signal-regulated kinase, p38 MAP kinases, and c-Jun N-terminal kinases.
The synthetic alkaloid ketazocine and terpenoid natural product salvinorin A are potent and selective KOR agonists. The KOR also mediates the dysphoria and hallucinations seen with opioids such as pentazocine.
- Asimadoline – peripherally-selective
- Bremazocine – highly selective
- Butorphanol – partial agonist
- Dynorphins (dynorphin A, dynorphin B, big dynorphin) – endogenous peptides
- FE 200665
- GR-89696 – selective for κ2
- Ibogaine – naturally-occurring
- ICI-204,448 – peripherally-selective
- LPK-26 – highly selective
- Menthol – naturally-occurring
- Morphine – naturally-occurring
- Nalbuphine – partial agonist
- Norbuprenorphine – partial agonist; peripherally-selective metabolite of buprenorphine
- Norbuprenorphine-3-glucuronide – metabolite of buprenorphine
- Oxycodone – selective for κ2b subtype
- Pentazocine – partial agonist
- Salvinorin A – naturally-occurring
- 2-Methoxymethyl salvinorin B – and its ethoxymethyl and fluoroethoxymethyl homologues
- 5'-Guanidinonaltrindole – selective, long-acting
- Amentoflavone – non-selective; naturally-occurring
- Binaltorphimine – selective, long-acting
- BU09059 – selective, short-acting; JDTic analogue
- Buprenorphine – non-selective; silent antagonist or weak partial agonist, depending on source
- Dezocine – non-selective; silent antagonist
- Diprenorphine – non-selective; maybe weak partial agonist
- JDTic – selective, long-acting
- LY-2456302 – selective, short-acting
- Methylnaltrexone – non-selective
- ML350 – selective, short-acting
- Nalmefene – non-selective
- Naloxone – non-selective
- Naltrexone – non-selective
- Noribogaine – non-selective; naturally-occurring
- Norbinaltorphimine – selective, long-acting
- PF-4455242 – selective, short-acting
- Quadazocine – non-selective; silent antagonist; preference for κ2
- Zyklophin – selective peptide antagonist; dynorphin A analogue
Found in numerous species of mint, (including peppermint, spearmint, and watermint), the naturally-occurring compound menthol is a weak KOR agonist owing to its antinociceptive, or pain blocking, effects in rats. In addition, mints can desensitize a region through the activation of TRPM8 receptors (the 'cold'/menthol receptor).
Used for the treatment of addiction in limited countries, ibogaine has become an icon of addiction management among certain underground circles. Despite its lack of addictive properties, ibogaine is listed as a Schedule I compound in the US because it is a psychoactive substance, hence it is considered illegal to possess under any circumstances. Ibogaine is also a KOR agonist and this property may contribute to the drug's anti-addictive efficacy.
Role in treatment of drug addiction
KOR agonists have recently been investigated for their therapeutic potential in the treatment of addiction and evidence points towards dynorphin, the endogenous KOR 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 MOR and KOR systems. In experimental "addiction" models the KOR has also been shown to influence stress-induced relapse to drug seeking behavior. For the drug dependent individual, risk of relapse is a major obstacle to becoming drug free. Recent reports demonstrated that KORs are required for stress-induced reinstatement of cocaine seeking.
One area of the brain most strongly associated with addiction is the nucleus accumbens (NAcc) and striatum while other structures that project to and from the NAcc also play a critical role. Though many other changes occur, addiction is often 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 putamen (striatum) and decreases of the same in the hypothalamus while the administration of a KOR agonist produced an opposite effect causing an increase in D2 receptors in the NAcc.
Additionally, while cocaine overdose victims showed a large increase in KORs (doubled) in the NAcc, KOR agonist administration is shown to be effective in decreasing cocaine seeking and self-administration. Furthermore, while cocaine abuse is associated with lowered prolactin response, KOR activation causes a release in prolactin, a hormone known for its important role in learning, neuronal plasticity and myelination.
It has also been reported that the KOR system is critical for stress-induced drug-seeking. In animal models, stress has been demonstrated to potentiate cocaine reward behavior in a kappa opioid-dependent manner. These effects are likely caused by stress-induced drug craving that requires activation of the KOR system. Although seemingly paradoxical, it is well known that drug taking results in a change from homeostasis to allostasis. It has been suggested that withdrawal-induced dysphoria or stress-induced dysphoria may act as a driving force by which the individual seeks alleviation via drug taking. The rewarding properties of drug are altered, and it is clear KOR activation following stress modulates the valence of drug to increase its rewarding properties and cause potentiation of reward behavior, or reinstatement to drug seeking. The stress-induced activation of KORs is likely due to multiple signaling mechanisms. The effects of KOR agonism on dopamine systems are well documented, and recent work also implicates the mitogen-activated protein kinase cascade and pCREB in KOR-dependent behaviors.
Though cocaine abuse is a frequently used model of addiction, KOR agonists have very marked effects on all types of addiction including alcohol, cocaine and opiate abuse. Not only are genetic differences in dynorphin receptor expression a marker for alcohol dependence but a single dose of a KOR antagonist markedly increased alcohol consumption in lab animals. There are numerous studies that reflect a reduction in self-administration of alcohol, and heroin dependence has also been shown to be effectively treated with KOR agonism by reducing the immediate rewarding effects and by causing the curative effect of up-regulation (increased production) of MORs that have been down-regulated during opioid abuse.
The anti-rewarding properties of KOR agonists are mediated through both long-term and short-term effects. The immediate effect of KOR agonism leads to reduction of dopamine release in the NAcc during self administration of cocaine and over the long term up-regulates receptors that have been down-regulated during substance abuse such as the MOR and the D2 receptor. These receptors modulate the release of other neurochemicals such as serotonin in the case of MOR agonists and acetylcholine in the case of D2. These changes can account for the physical and psychological remission of the pathology of addiction. The longer effects of KOR agonism (30 minutes or greater) have been linked to KOR-dependent stress-induced potentiation and reinstatement of drug seeking. It is hypothesized that these behaviors are mediated by KOR-dependent modulation of dopamine, serotonin, or norepinephrine and/or via activation of downstream signal transduction pathways.
Future clinical prospects
Selective KOR antagonists, including ALKS-5461 (a combination formulation of buprenorphine and samidorphan), and LY-2456302, are in clinical trials for the treatment of depression and drug addiction. JDTic and PF-4455242 were also under investigation but development was halted in both cases due to toxicity concerns (unrelated to their KOR antagonist properties).
- PDB 4DJH; Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC (March 2012). "Structure of the human κ-opioid receptor in complex with JDTic". Nature 485 (7398): 327–32. doi:10.1038/nature10939. PMC 3356457. PMID 22437504.
- James IF, Chavkin C, Goldstein A (1982). "Selectivity of dynorphin for kappa opioid receptors". Life Sci. 31 (12–13): 1331–4. doi:10.1016/0024-3205(82)90374-5. PMID 6128656.
- Fine PG, Portenoy RK (2004). "Chapter 2: The Endogenous Opioid System". A Clinical Guide to Opioid Analgesia. McGraw Hill.
- 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. doi:10.1016/0166-2236(95)93946-U. PMID 7535487.
- 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. doi:10.1021/jm00122a001. PMID 2536435.
- 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. doi:10.1016/0014-2999(89)90443-3. PMID 2553442.
- 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.
- Jordan BA, Devi LA (June 1999). "G-protein-coupled receptor heterodimerization modulates receptor function". Nature 399 (6737): 697–700. doi:10.1038/21441. PMC 3125690. PMID 10385123.
- Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (January 2008). "The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system". J. Neurosci. 28 (2): 407–14. doi:10.1523/JNEUROSCI.4458-07.2008. PMC 2612708. PMID 18184783.
- Xuei X, Dick D, Flury-Wetherill L, Tian HJ, Agrawal A, Bierut L, Goate A, Bucholz K, Schuckit M, Nurnberger J, Tischfield J, Kuperman S, Porjesz B, Begleiter H, Foroud T, Edenberg HJ (November 2006). "Association of the kappa-opioid system with alcohol dependence". Mol. Psychiatry 11 (11): 1016–24. doi:10.1038/sj.mp.4001882. PMID 16924269.
- Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB (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. PMC 129372. PMID 12192085.
- 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.
- 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. doi:10.1016/0014-2999(89)90495-0. PMID 2547626.
- 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.
- Tortella FC, Robles LC, Holaday JW (1986). "U50,488, a Highly Selective Kappa Opioid: Anticonvulsant Profile in Rats". The Journal of Pharmacology and Experimental Therapeutics 237 (1): 49–53. PMID 3007743.
- 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.
- 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. doi:10.1016/0006-2952(93)90394-C. PMID 8381004.
- 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. doi:10.1016/0014-2999(88)90094-5. PMID 2906610.
- 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.
- 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. doi:10.1016/0306-4522(94)90570-3. PMID 7700508.
- Bohn LM, Belcheva MM, Coscia CJ (February 2000). "Mitogenic signaling via endogenous kappa-opioid receptors in C6 glioma cells: evidence for the involvement of protein kinase C and the mitogen-activated protein kinase signaling cascade". J Neurochem 74 (2): 564–73. doi:10.1046/j.1471-4159.2000.740564.x. PMC 2504523. PMID 10646507.
- Belcheva MM, Clark AL, Haas PD, Serna JS, Hahn JW, Kiss A, Coscia CJ (July 2005). "Mu and kappa opioid receptors activate ERK/MAPK via different protein kinase C isoforms and secondary messengers in astrocytes". J. Biol. Chem. 280 (30): 27662–9. doi:10.1074/jbc.M502593200. PMC 1400585. PMID 15944153.
- Bruchas MR, Macey TA, Lowe JD, Chavkin C (June 2006). "Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes". J. Biol. Chem. 281 (26): 18081–9. doi:10.1074/jbc.M513640200. PMC 2096730. PMID 16648139.
- Bruchas MR, Xu M, Chavkin C (September 2008). "Repeated swim stress induces kappa opioid-mediated activation of extracellular signal-regulated kinase 1/2". NeuroReport 19 (14): 1417–22. doi:10.1097/WNR.0b013e32830dd655. PMC 2641011. PMID 18766023.
- Kam AY, Chan AS, Wong YH (July 2004). "Kappa-opioid receptor signals through Src and focal adhesion kinase to stimulate c-Jun N-terminal kinases in transfected COS-7 cells and human monocytic THP-1 cells". J. Pharmacol. Exp. Ther. 310 (1): 301–10. doi:10.1124/jpet.104.065078. PMID 14996948.
- Bruchas MR, Yang T, Schreiber S, Defino M, Kwan SC, Li S, Chavkin C (October 2007). "Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase". J. Biol. Chem. 282 (41): 29803–11. doi:10.1074/jbc.M705540200. PMC 2096775. PMID 17702750.
- 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. doi:10.1073/pnas.77.6.3691. PMC 349684. PMID 6251477.
- Holtzman SG (February 1985). "Drug discrimination studies". Drug Alcohol Depend 14 (3–4): 263–82. doi:10.1016/0376-8716(85)90061-4. PMID 2859972.
- Nielsen CK, Ross FB, Lotfipour S, Saini KS, Edwards SR, Smith MT (December 2007). "Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain". Pain 132 (3): 289–300. doi:10.1016/j.pain.2007.03.022. PMID 17467904.
- Wang Y, Chen Y, Xu W, Lee DY, Ma Z, Rawls SM, Cowan A, Liu-Chen LY (March 2008). "2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A". The Journal of Pharmacology and Experimental Therapeutics 324 (3): 1073–83. doi:10.1124/jpet.107.132142. PMC 2519046. PMID 18089845.
- Munro TA, Duncan KK, Xu W, Wang Y, Liu-Chen LY, Carlezon WA, Cohen BM, Béguin C (February 2008). "Standard protecting groups create potent and selective kappa opioids: salvinorin B alkoxymethyl ethers". Bioorganic & Medicinal Chemistry 16 (3): 1279–86. doi:10.1016/j.bmc.2007.10.067. PMC 2568987. PMID 17981041.
- Baker LE, Panos JJ, Killinger BA, Peet MM, Bell LM, Haliw LA, Walker SL (April 2009). "Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats". Psychopharmacology 203 (2): 203–11. doi:10.1007/s00213-008-1458-3. PMID 19153716.
- Katavic PL, Lamb K, Navarro H, Prisinzano TE (August 2007). "Flavonoids as opioid receptor ligands: identification and preliminary structure-activity relationships". J. Nat. Prod. 70 (8): 1278–82. doi:10.1021/np070194x. PMC 2265593. PMID 17685652.
- Casal-Dominquez, JJ; et al. (Jan 2014). "Characterization of BU09059: a novel potent selective κ-receptor antagonist.". ACS Chem Neurosci. (2014). doi:10.1021/cn4001507. PMID 24410326.
- Casal-Dominguez JJ, Furkert D, Ostovar M, et al. (March 2014). "Characterization of BU09059: a novel potent selective κ-receptor antagonist". ACS Chem Neurosci 5 (3): 177–84. doi:10.1021/cn4001507. PMID 24410326.
- Galeotti N, Di Cesare Mannelli L, Mazzanti G, Bartolini A, Ghelardini C (April 2002). "Menthol: a natural analgesic compound". Neurosci. Lett. 322 (3): 145–8. doi:10.1016/S0304-3940(01)02527-7. PMID 11897159.
- Werkheiser JL, Rawls SM, Cowan A (October 2006). "Mu and kappa opioid receptor agonists antagonize icilin-induced wet-dog shaking in rats". Eur. J. Pharmacol. 547 (1–3): 101–5. doi:10.1016/j.ejphar.2006.07.026. PMID 16945367.
- 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. doi:10.1124/jpet.106.112417. PMID 17060493.
- 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. doi:10.1124/jpet.103.059394. PMID 14718611.
- Glick SD, Maisonneuve IS (May 1998). "Mechanisms of antiaddictive actions of ibogaine". Annals of the New York Academy of Sciences 844: 214–26. doi:10.1111/j.1749-6632.1998.tb08237.x. PMID 9668680.
- 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. doi:10.1196/annals.1316.050. PMID 15542743.
- 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. doi:10.1016/j.neuropharm.2008.04.019. PMC 2577569. PMID 18538358.
- 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. doi:10.1124/jpet.107.129908. PMID 18203949.
- Beardsley PM, Howard JL, Shelton KL, Carroll FI (November 2005). "Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats". Psychopharmacology (Berl.) 183 (1): 118–26. doi:10.1007/s00213-005-0167-4. PMID 16184376.
- Redila VA, Chavkin C (September 2008). "Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system". Psychopharmacology (Berl.) 200 (1): 59–70. doi:10.1007/s00213-008-1122-y. PMC 2680147. PMID 18575850.
- 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. doi:10.1080/02791072.2000.10736099. PMID 11280926.
- 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. doi:10.1016/j.brainres.2007.04.074. PMID 17544385.
- 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 30 (1): 88–96. doi:10.1002/(SICI)1098-2396(199809)30:1<88::AID-SYN11>3.0.CO;2-L. PMID 9704885.
- 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. doi:10.1016/j.neuroscience.2006.09.008. PMID 17055175.
- 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. doi:10.1111/j.1749-6632.1999.tb09286.x. PMID 10415668.
- 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. doi:10.1007/s002130051016. PMID 10435406.
- 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. doi:10.1002/hup.780. PMID 16915581.
- 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. doi:10.1016/S0014-2999(01)01121-9. PMID 11448491.
- 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". Journal of Neuroscience 27 (8): 1812–23. doi:10.1523/JNEUROSCI.4441-06.2007. PMID 17314279.
- McLaughlin JP, Marton-Popovici M, Chavkin C. (July 2003). "Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses". Journal of Neuroscience 23 (13): 5674–83. PMC 2104777. PMID 12843270.
- Mash, DEBORAH C.; Li, S; Valdez, J; Chavkin, TA; Chavkin, C (June 2006). "Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system". Neuropsychopharmacology 31 (4): 787–94. doi:10.1038/sj.npp.1300872. PMC 2096774. PMID 16123746.
- Koob GF (July 2008). "A role for brain stress systems in addiction". Neuron 59 (1): 11–34. doi:10.1016/j.neuron.2008.06.012. PMC 2748830. PMID 18614026.
- Bruchas MR, Land BB, Aita M, Xu M, Barot SK, Li S, Chavkin C (2007). "Stress-induced p38 mitogen-activated protein kinase activation mediates -opioid-dependent dysphoria". J Neurosci 27 (43): 11614–23. doi:10.1523/JNEUROSCI.3769-07.2007. PMC 2481272. PMID 17959804.
- 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. doi:10.1007/s00213-005-0067-7. PMID 16001119.
- Walker BM, Koob GF (February 2008). "Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence". Neuropsychopharmacology 33 (3): 643–52. doi:10.1038/sj.npp.1301438. PMC 2739278. PMID 17473837.
- Xi ZX, Fuller SA, Stein EA (January 1998). "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. PMID 9435173.
- 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. doi:10.1046/j.1471-4159.2003.01754.x. PMID 12753076.
- 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. doi:10.1016/0304-3940(94)90559-2. PMID 7898771.
- Urbano M, Guerrero M, Rosen H, Roberts E (May 2014). "Antagonists of the kappa opioid receptor". Bioorg. Med. Chem. Lett. 24 (9): 2021–32. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494.
- Huang P, Steplock D, Weinman EJ, Hall RA, Ding Z, Li J, Wang Y, Liu-Chen LY (June 2004). "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". J. Biol. Chem. 279 (24): 25002–9. doi:10.1074/jbc.M313366200. PMID 15070904.
- Li JG, Chen C, Liu-Chen LY (July 2002). "Ezrin-radixin-moesin-binding phosphoprotein-50/Na+/H+ exchanger regulatory factor (EBP50/NHERF) blocks U50,488H-induced down-regulation of the human kappa opioid receptor by enhancing its recycling rate". J. Biol. Chem. 277 (30): 27545–52. doi:10.1074/jbc.M200058200. PMID 12004055.
- Li JG, Haines DS, Liu-Chen LY (April 2008). "Agonist-promoted Lys63-linked polyubiquitination of the human kappa-opioid receptor is involved in receptor down-regulation". Mol. Pharmacol. 73 (4): 1319–30. doi:10.1124/mol.107.042846. PMC 3489932. PMID 18212250.
- "Opioid Receptors: κ". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- kappa Opioid Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)