The KOR is a type of opioid receptor that binds the opioid peptidedynorphin as the primary endogenous ligand (substrate naturally occurring in the body). In addition to dynorphin, a variety of natural alkaloids, terpenes and other synthetic ligands bind to the receptor. The KOR may provide a natural addiction control mechanism, and therefore, drugs that target this receptor may have therapeutic potential in the treatment of addiction.
There is evidence that distribution and/or function of this receptor may differ between sexes.
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.
The claustrum is the region of the brain in which the KOR is most densely expressed. It has been proposed that this area, based on its structure and connectivity, has "a role in coordinating a set of diverse brain functions", and the claustrum has been elucidated as playing a crucial role in consciousness. As examples, lesions of the claustrum in humans are associated with disruption of consciousness and cognition, and electrical stimulation of the area between the insula and the claustrum has been found to produce an immediate loss of consciousness in humans along with recovery of consciousness upon cessation of the stimulation. On the basis of the preceding knowledge, it has been proposed that inhibition of the claustrum (as well as, "additionally, the deep layers of the cortex, mainly in prefrontal areas") by activation of KORs in these areas is primarily responsible for the profound consciousness-altering/dissociative hallucinogen effects of salvinorin A and other KOR agonists. In addition, it has been stated that "the subjective effects of S. divinorum indicate that salvia disrupts certain facets of consciousness much more than the largely serotonergic hallucinogen [LSD]", and it has been postulated that inhibition of a brain area that is apparently as fundamentally involved in consciousness and higher cognitive function as the claustrum may explain this. However, these conclusions are merely tentative, as "[KORs] are not exclusive to the claustrum; there is also a fairly high density of receptors located in the prefrontal cortex, hippocampus, nucleus accumbens and putamen", and "disruptions to other brain regions could also explain the consciousness-altering effects [of salvinorin A]".
In supplementation of the above, according to Addy et al.:
Theories suggest the claustrum may act to bind and integrate multisensory information, or else to encode sensory stimuli as salient or nonsalient (Mathur, 2014). One theory suggests the claustrum harmonizes and coordinates activity in various parts of the cortex, leading to the seamless integrated nature of subjective conscious experience (Crick and Koch, 2005; Stiefel et al., 2014). Disrupting claustral activity may lead to conscious experiences of disintegrated or unusually bound sensory information, perhaps including synesthesia. Such theories are in part corroborated by the fact that [salvia divinorum], which functions almost exclusively on the KOR system, can cause consciousness to be decoupled from external sensory input, leading to experiencing other environments and locations, perceiving other “beings” besides those actually in the room, and forgetting oneself and one’s body in the experience.
The depressive-like behaviors following prolonged morphine abstinence appear to be mediated by upregulation of the KOR/dynorphin system in the nucleus accumbens, as the local application of a KOR antagonist prevented the behaviors. As such, KOR antagonists might be useful for the treatment of depressive symptoms associated with opioid withdrawal.
A variety of other effects of KOR activation are known:
Activation of the KOR appears to antagonize many of the effects of the MOR, including analgesia, tolerance, euphoria, and memory regulation.Nalorphine and nalmefene are dual MOR antagonists and KOR agonists that have been used clinically as antidotes for opioid overdose, although the specific role and significance of KOR activation in this indication, if any, is uncertain. In any case however, KOR agonists notably do not affect respiratory drive, and hence do not reverse MOR activation-induced respiratory depression.
Eluxadoline is a peripherally restricted KOR agonist as well as MOR agonist and DOR antagonist that has been approved for the treatment of diarrhea-predominant irritable bowel syndrome. Asimadoline and fedotozine are selective and similarly peripherally restricted KOR agonists that were also investigated for the treatment of irritable bowel syndrome and reportedly demonstrated at least some efficacy for this indication but were ultimately never marketed.
KOR agonists are known for their characteristic diuretic effects, due to their negative regulation of vasopressin, also known as antidiuretic hormone (ADH).
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.
^Karkhanis A, Holleran KM, Jones SR (2017). "Dynorphin/Kappa Opioid Receptor Signaling in Preclinical Models of Alcohol, Drug, and Food Addiction". International Review of Neurobiology. 136: 53–88. doi:10.1016/bs.irn.2017.08.001. PMID29056156.
^Mansour A, Fox CA, Akil H, Watson SJ (January 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. PMID7535487.
^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". Journal of Medicinal Chemistry. 32 (2): 281–3. doi:10.1021/jm00122a001. PMID2536435.
^Mansson E, Bare L, Yang D (August 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. PMID8060324.
^ abcAddy PH, Garcia-Romeu A, Metzger M, Wade J (April 2015). "The subjective experience of acute, experimentally-induced Salvia divinorum inebriation". Journal of Psychopharmacology. 29 (4): 426–35. doi:10.1177/0269881115570081. PMID25691501.
^ abcdeChau A, Salazar AM, Krueger F, Cristofori I, Grafman J (November 2015). "The effect of claustrum lesions on human consciousness and recovery of function". Consciousness and Cognition. 36: 256–64. doi:10.1016/j.concog.2015.06.017. PMID26186439.
^Koubeissi MZ, Bartolomei F, Beltagy A, Picard F (August 2014). "Electrical stimulation of a small brain area reversibly disrupts consciousness". Epilepsy & Behavior. 37: 32–5. doi:10.1016/j.yebeh.2014.05.027. PMID24967698.
^ abXuei 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". Molecular Psychiatry. 11 (11): 1016–24. doi:10.1038/sj.mp.4001882. PMID16924269.
^ abZan GY, Wang Q, Wang YJ, Liu Y, Hang A, Shu XH, Liu JG (September 2015). "Antagonism of κ opioid receptor in the nucleus accumbens prevents the depressive-like behaviors following prolonged morphine abstinence". Behavioural Brain Research. 291: 334–41. doi:10.1016/j.bbr.2015.05.053. PMID26049060.
^Yamada K, Imai M, Yoshida S (January 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. PMID2547626.
^Zeynalov E, Nemoto M, Hurn PD, Koehler RC, Bhardwaj A (March 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. PMID16049424.
^Tortella FC, Robles L, Holaday JW (April 1986). "U50,488, a highly selective kappa opioid: anticonvulsant profile in rats". The Journal of Pharmacology and Experimental Therapeutics. 237 (1): 49–53. PMID3007743.
^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". The Journal of Pharmacology and Experimental Therapeutics. 266 (3): 1678–83. PMID8103800.
^Konkoy CS, Childers SR (January 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. PMID8381004.
^Schoffelmeer AN, Rice KC, Jacobson AE, Van Gelderen JG, Hogenboom F, Heijna MH, Mulder AH (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". European Journal of Pharmacology. 154 (2): 169–78. doi:10.1016/0014-2999(88)90094-5. PMID2906610.
^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". Molecular Pharmacology. 47 (3): 551–7. PMID7700253.
^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. PMID7700508.
^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". The Journal of Pharmacology and Experimental Therapeutics. 310 (1): 301–10. doi:10.1124/jpet.104.065078. PMID14996948.
^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. PMID17467904.
^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. PMID19153716.
^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. PMID14718611.
^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. PMID15542743.
^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. PMID18203949.
^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. 183 (1): 118–26. doi:10.1007/s00213-005-0167-4. PMID16184376.
^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. PMID11280926.
^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. PMID17544385.
^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. PMID17055175.
^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. PMID16915581.
^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. PMID11448491.
^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. 27 (8): 1812–23. doi:10.1523/JNEUROSCI.4441-06.2007. PMID17314279.
^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. PMID9435173.
^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. PMID12753076.
^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. PMID7898771.
^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". The Journal of Biological Chemistry. 279 (24): 25002–9. doi:10.1074/jbc.M313366200. PMID15070904.
^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". The Journal of Biological Chemistry. 277 (30): 27545–52. doi:10.1074/jbc.M200058200. PMID12004055.