|Opioid receptor, kappa 1|
|Symbols||; K-OR-1; KOR; KOR-1; 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.  More recent studies have shown the aversive properties in a variety of ways.
Some 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, mescaline or psilocybin.
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.
- Alazocine– partial agonist
- Asimadoline – peripherally-selective
- Bremazocine – highly selective
- Butorphanol – partial agonist
- CR665 – peripherally-selective
- Cyclazocine – partial agonist
- Difelikefalin (CR845) – peripherally-selective
- Dynorphins (dynorphin A, dynorphin B, big dynorphin) – endogenous peptides
- Erinacine E
- GR-89696 – selective for κ2
- Ibogaine – naturally-occurring
- ICI-204,448 – peripherally-selective
- LPK-26 – highly selective
- Menthol – naturally-occurring
- Metazocine – partial agonist
- Morphine – naturally-occurring
- Nalbuphine – partial agonist
- Nalmefene – partial agonist
- Nalorphine – partial agonist
- Norbuprenorphine – partial agonist; peripherally-selective metabolite of buprenorphine
- Norbuprenorphine-3-glucuronide – likely partial agonist; peripherally-selective metabolite of buprenorphine
- Oxycodone – selective for κ2b subtype
- Pentazocine – partial agonist
- RB-64 (22-thiocyanatosalvinorin A) – G protein biased agonist with a bias factor of 96
- Salvinorin A – naturally-occurring
- 2-Methoxymethyl salvinorin B – and its ethoxymethyl and fluoroethoxymethyl homologues
- Xorphanol – partial agonist
- 5'-Acetamidinoethylnaltrindole (ANTI) – selective
- 5'-Guanidinonaltrindole (5'-GNTI) – selective, long-acting
- Amentoflavone – non-selective; naturally-occurring
- AT-076 – non-selective, likely long acting; JDTic analogue
- Binaltorphimine – selective, long-acting
- BU09059 – selective, short-acting; JDTic analogue
- Buprenorphine – non-selective; silent antagonist or weak partial agonist, depending on source
- CERC-501 – selective, short-acting
- Dezocine – non-selective; silent antagonist
- DIPPA – selective, long-acting
- Diprenorphine – non-selective; maybe weak partial agonist
- JDTic – selective, long-acting
- LY-255582 - non-selective
- LY-2459989 – selective, short-acting
- LY-2795050 – selective, short-acting
- Methylnaltrexone – non-selective
- ML190 – selective
- ML350 – selective, short-acting
- MR-2266 – non-selective
- Naloxone – non-selective
- Naltrexone – non-selective
- Noribogaine – non-selective; naturally-occurring
- Norbinaltorphimine – selective, long-acting
- Pawhuskin A – selective; naturally-occurring
- 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 CERC-501 (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).
- "Structure of the human ?-opioid receptor in complex with JDTic". Nature 485 (7398): 327–32. doi:10.1038/nature10939. PMC 3356457. PMID 22437504.; 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).
- James IF, Chavkin C, Goldstein A (1982). "Selectivity of dynorphin for kappa opioid receptors". Life Sciences 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" (PDF). A Clinical Guide to Opioid Analgesia. McGraw Hill.
- Mansour A, Fox CA, Akil H, Watson SJ (Jan 1995). "Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications". Trends in Neurosciences 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 (Feb 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". Journal of Medicinal Chemistry 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 (Aug 1989). "Pharmacological activities of optically pure enantiomers of the kappa opioid agonist, U50,488, and its cis diastereomer: evidence for three kappa receptor subtypes". European Journal of Pharmacology 167 (3): 345–53. doi:10.1016/0014-2999(89)90443-3. PMID 2553442.
- Mansson E, Bare L, Yang D (Aug 1994). "Isolation of a human kappa opioid receptor cDNA from placenta". Biochemical and Biophysical Research Communications 202 (3): 1431–7. doi:10.1006/bbrc.1994.2091. PMID 8060324.
- Jordan BA, Devi LA (Jun 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 (Jan 2008). "The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system". The Journal of Neuroscience 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 (Nov 2006). "Association of the kappa-opioid system with alcohol dependence". Molecular 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 (Sep 2002). "Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist". Proceedings of the National Academy of Sciences of the United States of America 99 (18): 11934–9. doi:10.1073/pnas.182234399. PMC 129372. PMID 12192085.
- Pan ZZ (Mar 1998). "mu-Opposing actions of the kappa-opioid receptor". Trends in Pharmacological Sciences 19 (3): 94–8. doi:10.1016/S0165-6147(98)01169-9. PMID 9584625.
- Yamada K, Imai M, Yoshida S (Jan 1989). "Mechanism of diuretic action of U-62,066E, a kappa opioid receptor agonist". European Journal of Pharmacology 160 (2): 229–37. doi:10.1016/0014-2999(89)90495-0. PMID 2547626.
- Zeynalov E, Nemoto M, Hurn PD, Koehler RC, Bhardwaj A (Mar 2006). "Neuroprotective effect of selective kappa opioid receptor agonist is gender specific and linked to reduced neuronal nitric oxide". Journal of Cerebral Blood Flow and Metabolism 26 (3): 414–20. doi:10.1038/sj.jcbfm.9600196. PMID 16049424.
- Tortella FC, Robles L, Holaday JW (Apr 1986). "U50,488, a highly selective kappa opioid: anticonvulsant profile in rats" (PDF). The Journal of Pharmacology and Experimental Therapeutics 237 (1): 49–53. PMID 3007743.
- Lawrence DM, Bidlack JM (Sep 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". The Journal of Pharmacology and Experimental Therapeutics 266 (3): 1678–83. PMID 8103800.
- Konkoy CS, Childers SR (Jan 1993). "Relationship between kappa 1 opioid receptor binding and inhibition of adenylyl cyclase in guinea pig brain membranes". Biochemical Pharmacology 45 (1): 207–16. doi:10.1016/0006-2952(93)90394-C. PMID 8381004.
- Schoffelmeer AN, Rice KC, Jacobson AE, Van Gelderen JG, Hogenboom F, Heijna MH, Mulder AH (Sep 1988). "Mu-, delta- and kappa-opioid receptor-mediated inhibition of neurotransmitter release and adenylate cyclase activity in rat brain slices: studies with fentanyl isothiocyanate". European Journal of Pharmacology 154 (2): 169–78. doi:10.1016/0014-2999(88)90094-5. PMID 2906610.
- Henry DJ, Grandy DK, Lester HA, Davidson N, Chavkin C (Mar 1995). "Kappa-opioid receptors couple to inwardly rectifying potassium channels when coexpressed by Xenopus oocytes". Molecular Pharmacology 47 (3): 551–7. PMID 7700253.
- Tallent M, Dichter MA, Bell GI, Reisine T (Dec 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 (Feb 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". Journal of Neurochemistry 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 (Jul 2005). "Mu and kappa opioid receptors activate ERK/MAPK via different protein kinase C isoforms and secondary messengers in astrocytes". The Journal of Biological Chemistry 280 (30): 27662–9. doi:10.1074/jbc.M502593200. PMC 1400585. PMID 15944153.
- Bruchas MR, Macey TA, Lowe JD, Chavkin C (Jun 2006). "Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes". The Journal of Biological Chemistry 281 (26): 18081–9. doi:10.1074/jbc.M513640200. PMC 2096730. PMID 16648139.
- Bruchas MR, Xu M, Chavkin C (Sep 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 (Jul 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". The Journal of Pharmacology and Experimental Therapeutics 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 (Oct 2007). "Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase". The Journal of Biological Chemistry 282 (41): 29803–11. doi:10.1074/jbc.M705540200. PMC 2096775. PMID 17702750.
- Pasternak GW (Jun 1980). "Multiple opiate receptors: [3H]ethylketocyclazocine receptor binding and ketocyclazocine analgesia". Proceedings of the National Academy of Sciences of the United States of America 77 (6): 3691–4. doi:10.1073/pnas.77.6.3691. PMC 349684. PMID 6251477.
- Holtzman SG (Feb 1985). "Drug discrimination studies". Drug and Alcohol Dependence 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 (Dec 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.
- White KL, Robinson JE, Zhu H, DiBerto JF, Polepally PR, Zjawiony JK, Nichols DE, Malanga CJ, Roth BL (Jan 2015). "The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo". The Journal of Pharmacology and Experimental Therapeutics 352 (1): 98–109. doi:10.1124/jpet.114.216820. PMID 25320048.
- Wang Y, Chen Y, Xu W, Lee DY, Ma Z, Rawls SM, Cowan A, Liu-Chen LY (Mar 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 (Feb 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 (Apr 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 (Aug 2007). "Flavonoids as opioid receptor ligands: identification and preliminary structure-activity relationships". Journal of Natural Products 70 (8): 1278–82. doi:10.1021/np070194x. PMC 2265593. PMID 17685652.
- Casal-Dominguez JJ, Furkert D, Ostovar M, Teintang L, Clark MJ, Traynor JR, Husbands SM, Bailey SJ (Mar 2014). "Characterization of BU09059: a novel potent selective κ-receptor antagonist". ACS Chemical Neuroscience 5 (3): 177–84. doi:10.1021/cn4001507. PMID 24410326.
- Casal-Dominguez JJ, Furkert D, Ostovar M, Teintang L, Clark MJ, Traynor JR, Husbands SM, Bailey SJ (Mar 2014). "Characterization of BU09059: a novel potent selective κ-receptor antagonist". ACS Chemical Neuroscience 5 (3): 177–84. doi:10.1021/cn4001507. PMID 24410326.
- Hartung AM, Beutler JA, Navarro HA, Wiemer DF, Neighbors JD (Feb 2014). "Stilbenes as κ-selective, non-nitrogenous opioid receptor antagonists". Journal of Natural Products 77 (2): 311–9. doi:10.1021/np4009046. PMID 24456556.
- Galeotti N, Di Cesare Mannelli L, Mazzanti G, Bartolini A, Ghelardini C (Apr 2002). "Menthol: a natural analgesic compound". Neuroscience Letters 322 (3): 145–8. doi:10.1016/S0304-3940(01)02527-7. PMID 11897159.
- Werkheiser JL, Rawls SM, Cowan A (Oct 2006). "Mu and kappa opioid receptor agonists antagonize icilin-induced wet-dog shaking in rats". European Journal of Pharmacology 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 (Jan 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 (Mar 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 (Oct 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 (Jul 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 (Apr 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 (Nov 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 183 (1): 118–26. doi:10.1007/s00213-005-0167-4. PMID 16184376.
- Redila VA, Chavkin C (Sep 2008). "Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system". Psychopharmacology 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 (Nov 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 (Jul 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 (Sep 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 (Jan 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 (Jun 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 (Jun 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 (Aug 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 (Jul 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 (Feb 2007). "White matter plasticity and enhanced remyelination in the maternal CNS". The Journal of Neuroscience 27 (8): 1812–23. doi:10.1523/JNEUROSCI.4441-06.2007. PMID 17314279.
- McLaughlin JP, Marton-Popovici M, Chavkin C (Jul 2003). "Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses". The Journal of Neuroscience 23 (13): 5674–83. PMC 2104777. PMID 12843270.
- McLaughlin JP, Li S, Valdez J, Chavkin TA, Chavkin C (Jun 2006). "Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system". Neuropsychopharmacology 31 (6): 1241–8. doi:10.1038/sj.npp.1300872. PMC 2096774. PMID 16123746.
- Koob GF (Jul 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 (Oct 2007). "Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria". The Journal of Neuroscience 27 (43): 11614–23. doi:10.1523/JNEUROSCI.3769-07.2007. PMC 2481272. PMID 17959804.
- Mitchell JM, Liang MT, Fields HL (Nov 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 (Feb 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 (Jan 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 (Jun 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 (Nov 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". Bioorganic & Medicinal Chemistry Letters 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 (Jun 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". The Journal of Biological Chemistry 279 (24): 25002–9. doi:10.1074/jbc.M313366200. PMID 15070904.
- Li JG, Chen C, Liu-Chen LY (Jul 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". The Journal of Biological Chemistry 277 (30): 27545–52. doi:10.1074/jbc.M200058200. PMID 12004055.
- Li JG, Haines DS, Liu-Chen LY (Apr 2008). "Agonist-promoted Lys63-linked polyubiquitination of the human kappa-opioid receptor is involved in receptor down-regulation". Molecular Pharmacology 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)