View source for Biology:Κ-opioid receptor

{{Short description|Protein-coding gene in the species Homo sapiens, named for ketazocine}}
{{lowercase title}}
{{Infobox_gene}}

The '''κ-opioid receptor''' or '''kappa opioid receptor''', abbreviated '''KOR''' or '''KOP''' for its ligand [[Chemistry:Ketazocine|ketazocine]], is a [[Biology:G protein-coupled receptor|G protein-coupled receptor]] that in humans is encoded by the ''OPRK1'' [[Biology:Gene|gene]]. The KOR is coupled to the [[Biology:G protein|G protein]] [[Biology:Gi alpha subunit|G<sub>i</sub>/G<sub>0</sub>]] and is one of four related [[Biology:Receptor (biochemistry)|receptors]] that bind [[Chemistry:Opioid|opioid]]-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering [[Biology:Nociception|nociception]], [[Philosophy:Consciousness|consciousness]], [[Engineering:Motor control|motor control]], and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.<ref name="Anderson_2017">{{cite journal | vauthors = Anderson RI, Becker HC | title = Role of the Dynorphin/Kappa Opioid Receptor System in the Motivational Effects of Ethanol | journal = Alcoholism: Clinical and Experimental Research | volume = 41 | issue = 8 | pages = 1402–1418 | date = August 2017 | pmid = 28425121 | doi = 10.1111/acer.13406 | pmc = 5522623 }}</ref><ref name="Karkhanis_2017">{{cite journal | vauthors = Karkhanis A, Holleran KM, Jones SR | title = Dynorphin/Kappa Opioid Receptor Signaling in Preclinical Models of Alcohol, Drug, and Food Addiction | journal = International Review of Neurobiology | volume = 136 | pages = 53–88 | date = 2017 | pmid = 29056156 | doi = 10.1016/bs.irn.2017.08.001 | isbn = 9780128124734 }}</ref>

The KOR is a type of [[Biology:Opioid receptor|opioid receptor]] that binds the [[Biology:Opioid peptide|opioid peptide]] [[Biology:Dynorphin|dynorphin]] as the primary [[Biology:Ligand (biochemistry)|endogenous ligand]] (substrate naturally occurring in the body).<ref name="pmid6128656">{{cite journal | vauthors = James IF, Chavkin C, Goldstein A | title = Selectivity of dynorphin for kappa opioid receptors | journal = Life Sciences | volume = 31 | issue = 12–13 | pages = 1331–4 | year = 1982 | pmid = 6128656 | doi = 10.1016/0024-3205(82)90374-5 }}</ref> In addition to dynorphin, a variety of natural [[Chemistry:Alkaloid|alkaloid]]s, terpenes and  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 {{Citation needed|date=January 2024}}.

There is evidence that distribution and/or function of this receptor may differ between sexes.<ref name="Chartoff_Mavrikaki_2015">{{cite journal | vauthors = Chartoff EH, Mavrikaki M | title = Sex Differences in Kappa Opioid Receptor Function and Their Potential Impact on Addiction | journal = Frontiers in Neuroscience | volume = 9 | pages = 466 | year = 2015 | pmid = 26733781 | pmc = 4679873 | doi = 10.3389/fnins.2015.00466 | doi-access = free }}</ref><ref name="pmid20951148">{{cite journal | vauthors = Rasakham K, Liu-Chen LY | title = Sex differences in kappa opioid pharmacology | journal = Life Sciences | volume = 88 | issue = 1–2 | pages = 2–16 | date = January 2011 | pmid = 20951148 | pmc = 3870184 | doi = 10.1016/j.lfs.2010.10.007 }}</ref><ref>{{cite journal | vauthors = Siciliano CA, Calipari ES, Yorgason JT, Lovinger DM, Mateo Y, Jimenez VA, Helms CM, Grant KA, Jones SR | title = Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques | journal = Psychopharmacology | volume = 233 | issue = 8 | pages = 1435–43 | date = April 2016 | pmid = 26892380 | doi = 10.1007/s00213-016-4239-4 | pmc = 4814331 }}</ref><ref>{{cite journal | vauthors = Johnson BN, Kumar A, Su Y, Singh S, Sai KK, Nader SH, Li S, Reboussin BA, Huang Y, Deep G, Nader MA | display-authors = 6 | title = PET imaging of kappa opioid receptors and receptor expression quantified in neuron-derived extracellular vesicles in socially housed female and male cynomolgus macaques | journal = Neuropsychopharmacology | date = September 2022 | volume = 48 | issue = 2 | pages = 410–417 | pmid = 36100655 | doi = 10.1038/s41386-022-01444-9 | pmc = 9751296 }}</ref>

== Distribution ==
KORs are widely distributed in the [[Biology:Brain|brain]], [[Biology:Spinal cord|spinal cord]] ([[Biology:Substantia gelatinosa of Rolando|substantia gelatinosa]]), and in peripheral tissues. High levels of the receptor have been detected in the [[Biology:Prefrontal cortex|prefrontal cortex]], periaqueductal gray, [[Chemistry:Raphe nuclei|raphe nuclei]] ([[Chemistry:Dorsal raphe nucleus|dorsal]]), [[Chemistry:Ventral tegmental area|ventral tegmental area]], [[Biology:Substantia nigra|substantia nigra]], dorsal striatum ([[Biology:Putamen|putamen]], [[Biology:Caudate nucleus|caudate]]), ventral striatum ([[Biology:Nucleus accumbens|nucleus accumbens]], [[Biology:Olfactory tubercle|olfactory tubercle]]), [[Medicine:Amygdala|amygdala]], [[Biology:Stria terminalis|bed nucleus stria terminalis]], [[Biology:Claustrum|claustrum]], [[Biology:Hippocampus|hippocampus]], [[Biology:Hypothalamus|hypothalamus]], midline thalamic nuclei, locus coeruleus, spinal trigeminal nucleus, parabrachial nucleus, and solitary nucleus.<ref name="WangSun2010">{{cite journal | vauthors = Wang YH, Sun JF, Tao YM, Chi ZQ, Liu JG | title = The role of kappa-opioid receptor activation in mediating antinociception and addiction | journal = Acta Pharmacologica Sinica | volume = 31 | issue = 9 | pages = 1065–70 | date = September 2010 | pmid = 20729876 | doi = 10.1038/aps.2010.138 | pmc=4002313}}</ref><ref name="pmid7535487">{{cite journal | vauthors = Mansour A, Fox CA, Akil H, Watson SJ | title = Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications | journal = Trends in Neurosciences | volume = 18 | issue = 1 | pages = 22–9 | date = January 1995 | pmid = 7535487 | doi = 10.1016/0166-2236(95)93946-U | s2cid = 300974 }}</ref>

== Subtypes ==
Based on receptor binding studies, three variants of the KOR designated κ<sub>1</sub>, κ<sub>2</sub>, and κ<sub>3</sub> have been characterized.<ref name="pmid2536435">{{cite journal | vauthors = de Costa BR, Rothman RB, Bykov V, Jacobson AE, Rice KC | title = Selective and enantiospecific acylation of kappa opioid receptors by (1S,2S)-trans-2-isothiocyanato-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexy l] benzeneacetamide. Demonstration of kappa receptor heterogeneity | journal = Journal of Medicinal Chemistry | volume = 32 | issue = 2 | pages = 281–3 | date = February 1989 | pmid = 2536435 | doi = 10.1021/jm00122a001 }}</ref><ref name="pmid2553442">{{cite journal | vauthors = Rothman RB, France CP, Bykov V, De Costa BR, Jacobson AE, Woods JH, Rice KC | title = Pharmacological activities of optically pure enantiomers of the kappa opioid agonist, U50,488, and its cis diastereomer: evidence for three kappa receptor subtypes | journal = European Journal of Pharmacology | volume = 167 | issue = 3 | pages = 345–53 | date = August 1989 | pmid = 2553442 | doi = 10.1016/0014-2999(89)90443-3 | hdl = 2027.42/27799 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/27799/1/0000199.pdf | hdl-access = free }}</ref> However, only one [[Biology:Complementary DNA|cDNA]] clone has been identified,<ref name="pmid8060324">{{cite journal | vauthors = Mansson E, Bare L, Yang D | title = Isolation of a human kappa opioid receptor cDNA from placenta | journal = Biochemical and Biophysical Research Communications | volume = 202 | issue = 3 | pages = 1431–7 | date = August 1994 | pmid = 8060324 | doi = 10.1006/bbrc.1994.2091 }}</ref> hence these receptor subtypes likely arise from interaction of one KOR protein with other membrane associated proteins.<ref name="pmid10385123">{{cite journal | vauthors = Jordan BA, Devi LA | title = G-protein-coupled receptor heterodimerization modulates receptor function | journal = Nature | volume = 399 | issue = 6737 | pages = 697–700 | date = June 1999 | pmid = 10385123 | pmc = 3125690 | doi = 10.1038/21441 | bibcode = 1999Natur.399..697J }}</ref>

== Function ==
===Pain===
Similarly to μ-opioid receptor (MOR) agonists, KOR agonists are potently [[Biology:Analgesic|analgesic]], and have been employed clinically in the treatment of [[Medicine:Pain|pain]]. However, KOR agonists also produce [[Medicine:Side effect|side effect]]s such as [[Medicine:Dysphoria|dysphoria]], [[Unsolved:Hallucination|hallucination]]s, and [[Medicine:Dissociation (psychology)|dissociation]], which has limited their clinical usefulness.<ref name="pmid18184783">{{cite journal | vauthors = Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C | title = The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system | journal = The Journal of Neuroscience | volume = 28 | issue = 2 | pages = 407–14 | date = January 2008 | pmid = 18184783 | pmc = 2612708 | doi = 10.1523/JNEUROSCI.4458-07.2008 }}</ref> Examples of KOR agonists that have been used medically as analgesics include [[Chemistry:Butorphanol|butorphanol]], [[Chemistry:Nalbuphine|nalbuphine]], [[Chemistry:Levorphanol|levorphanol]], [[Chemistry:Levallorphan|levallorphan]], [[Chemistry:Pentazocine|pentazocine]], [[Chemistry:Phenazocine|phenazocine]], and [[Chemistry:Eptazocine|eptazocine]]. [[Chemistry:Difelikefalin|Difelikefalin]] (CR845, FE-202845) and [[Chemistry:CR665|CR665]] (FE-200665, JNJ-38488502) are peripherally restricted KOR agonists lacking the CNS side effects of centrally active KOR agonists and are currently under clinical investigation as analgesics.

=== Consciousness ===
Centrally active KOR agonists have [[Unsolved:Hallucinogen|hallucinogen]]ic or dissociative effects, as exemplified by [[Chemistry:Salvinorin A|salvinorin A]] (the active constituent in ''[[Biology:Salvia divinorum|Salvia divinorum]]''). These effects are generally undesirable in medicinal drugs. It is thought that the hallucinogenic and dysphoric effects of opioids such as [[Chemistry:Butorphanol|butorphanol]], [[Chemistry:Nalbuphine|nalbuphine]], and [[Chemistry:Pentazocine|pentazocine]] serve to limit their abuse potential. In the case of salvinorin A, a structurally novel neoclerodane [[Chemistry:Diterpene|diterpene]] KOR agonist, these hallucinogenic effects are sought by recreational users, despite the dysphoria experienced by some users.  Another KOR agonist with comparable effects is [[Biology:Ibogaine|ibogaine]], which has possible medical application in addiction treatment. While these KOR agonists possess hallucinogenic and dissociative effects, they are mechanistically and qualitatively different from those of the [[Biology:5-HT2A receptor|5HT2AR]] agonist [[Chemistry:Psychedelic drug|psychedelic hallucinogens]] such as [[Chemistry:Lysergic acid diethylamide|lysergic acid diethylamide]] (LSD) or [[Chemistry:Psilocybin|psilocybin]] and those of [[Chemistry:NMDA receptor antagonist|NMDAR antagonist]] dissociatives/anesthetics [[Chemistry:Ketamine|ketamine]] and [[Chemistry:Phencyclidine|phencyclidine]].<ref name="pmid12192085">{{cite journal| vauthors = Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB | title = Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 18 | pages = 11934–9 | date = September 2002 | pmid = 12192085 | pmc = 129372 | doi = 10.1073/pnas.182234399 | bibcode = 2002PNAS...9911934R | doi-access = free }}</ref>

The [[Biology:Claustrum|claustrum]] is the region of the brain in which the KOR is most densely expressed.<ref name="AddyGarcia-Romeu2015">{{cite journal | vauthors = Addy PH, Garcia-Romeu A, Metzger M, Wade J | title = The subjective experience of acute, experimentally-induced Salvia divinorum inebriation | journal = Journal of Psychopharmacology | volume = 29 | issue = 4 | pages = 426–35 | date = April 2015 | pmid = 25691501 | doi = 10.1177/0269881115570081 | s2cid = 34171297 }}</ref><ref name="StiefelMerrifield2014">{{cite journal | vauthors = Stiefel KM, Merrifield A, Holcombe AO | title = The claustrum's proposed role in consciousness is supported by the effect and target localization of Salvia divinorum | journal = Frontiers in Integrative Neuroscience | volume = 8 | pages = 20 | year = 2014 | pmid = 24624064 | doi = 10.3389/fnint.2014.00020 | pmc=3935397| doi-access = free }}</ref><ref name="ChauSalazar2015">{{cite journal | vauthors = Chau A, Salazar AM, Krueger F, Cristofori I, Grafman J | title = The effect of claustrum lesions on human consciousness and recovery of function | journal = Consciousness and Cognition | volume = 36 | pages = 256–64 | date = November 2015 | pmid = 26186439 | doi = 10.1016/j.concog.2015.06.017 | s2cid = 46139982 }}</ref> 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 [[Philosophy:Consciousness|consciousness]].<ref name="StiefelMerrifield2014" /><ref name="ChauSalazar2015" /> As examples, lesions of the claustrum in humans are associated with disruption of consciousness and cognition, and electrical stimulation of the area between the [[Biology:Insular cortex|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.<ref name="ChauSalazar2015" /><ref name="KoubeissiBartolomei2014">{{cite journal | vauthors = Koubeissi MZ, Bartolomei F, Beltagy A, Picard F | title = Electrical stimulation of a small brain area reversibly disrupts consciousness | journal = Epilepsy & Behavior | volume = 37 | pages = 32–5 | date = August 2014 | pmid = 24967698 | doi = 10.1016/j.yebeh.2014.05.027 | s2cid = 8368944 }}</ref> 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.<ref name="StiefelMerrifield2014" /><ref name="ChauSalazar2015" /> 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.<ref name="StiefelMerrifield2014" /> 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]".<ref name="ChauSalazar2015" />

In supplementation of the above, according to Addy et al.:<ref name="AddyGarcia-Romeu2015" />

{{Blockquote|''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 [[Philosophy:Synesthesia|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.''<ref name="AddyGarcia-Romeu2015" />}}

===Mood, stress, and addiction===
The involvement of the KOR in stress, as well as in consequences of [[Medicine:Chronic stress|chronic stress]] such as [[Medicine:Depression (mood)|depression]], [[Medicine:Anxiety|anxiety]], [[Medicine:Anhedonia|anhedonia]], and increased drug-seeking behavior, has been made clear.<ref name="pmid18184783"/> KOR agonists are notably dysphoric and aversive at sufficient doses.<ref name="pmid16924269">{{cite journal | vauthors = 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 | title = Association of the kappa-opioid system with alcohol dependence | journal = Molecular Psychiatry | volume = 11 | issue = 11 | pages = 1016–24 | date = November 2006 | pmid = 16924269 | doi = 10.1038/sj.mp.4001882 | doi-access = free }}</ref> The KOR antagonists [[Chemistry:Buprenorphine|buprenorphine]], as ALKS-5461 (a combination formulation with [[Chemistry:Samidorphan|samidorphan]]), and [[Chemistry:CERC-501|CERC-501]] (LY-2456302) are currently in clinical development for the treatment of major depressive disorder and [[Medicine:Substance use disorder|substance use disorder]]s.<ref name="pmid24690494">{{cite journal | vauthors = Urbano M, Guerrero M, Rosen H, Roberts E | title = Antagonists of the kappa opioid receptor | journal = Bioorganic & Medicinal Chemistry Letters | volume = 24 | issue = 9 | pages = 2021–32 | date = May 2014 | pmid = 24690494 | doi = 10.1016/j.bmcl.2014.03.040 }}</ref> [[Chemistry:JDTic|JDTic]] and [[Chemistry:PF-4455242|PF-4455242]] were also under investigation but development was halted in both cases due to [[Medicine:Toxicity|toxicity]] concerns.<ref name="pmid24690494" />

The depressive-like behaviors following prolonged [[Biology:Morphine|morphine]] abstinence appear to be mediated by upregulation of the KOR/dynorphin system in the [[Biology:Nucleus accumbens|nucleus accumbens]], as the local application of a KOR antagonist prevented the behaviors.<ref name="pmid26049060">{{cite journal | vauthors = Zan GY, Wang Q, Wang YJ, Liu Y, Hang A, Shu XH, Liu JG | title = Antagonism of κ opioid receptor in the nucleus accumbens prevents the depressive-like behaviors following prolonged morphine abstinence | journal = Behavioural Brain Research | volume = 291 | pages = 334–41 | date = September 2015 | pmid = 26049060 | doi = 10.1016/j.bbr.2015.05.053 | s2cid = 32817749 }}</ref> As such, KOR antagonists might be useful for the treatment of depressive symptoms associated with [[Chemistry:Opioid withdrawal|opioid withdrawal]].<ref name="pmid26049060" />

In a small clinical study, [[Chemistry:Pentazocine|pentazocine]], a KOR agonist, was found to rapidly and substantially reduce symptoms of [[Medicine:Mania|mania]] in patients with [[Medicine:Bipolar disorder|bipolar disorder]].<ref name="Chartoff_Mavrikaki_2015" /> It was postulated that the efficacy observed was due to KOR activation-mediated amelioration of excessive [[Chemistry:Dopaminergic|dopaminergic]] signaling in the reward pathways.<ref name="Chartoff_Mavrikaki_2015" />{{Failed verification|date=July 2019}}

=== Others ===
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, [[Chemistry:Opioid#Tolerance|tolerance]], [[Chemistry:Euphoria|euphoria]], and [[Memory|memory]] regulation.<ref name="pmid9584625">{{cite journal | vauthors = Pan ZZ | title = mu-Opposing actions of the kappa-opioid receptor | journal = Trends in Pharmacological Sciences | volume = 19 | issue = 3 | pages = 94–8 | date = March 1998 | pmid = 9584625 | doi = 10.1016/S0165-6147(98)01169-9 }}</ref> [[Chemistry:Nalorphine|Nalorphine]] and [[Chemistry:Nalmefene|nalmefene]] are dual MOR antagonists and KOR agonists that have been used clinically as [[Chemistry:Antidote|antidote]]s 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.<ref name="KayeVadivelu2014">{{cite book | vauthors = Kaye AD, Vadivelu N, Urman RD |title=Substance Abuse: Inpatient and Outpatient Management for Every Clinician|url=https://books.google.com/books?id=ms2lBQAAQBAJ&pg=PA181|date=1 December 2014|publisher=Springer|isbn=978-1-4939-1951-2|pages=181–}}</ref>
* KOR agonists suppress itching, and the selective KOR agonist [[Chemistry:Nalfurafine|nalfurafine]] is used clinically as an antipruritic (anti-itch drug).
* [[Chemistry:Eluxadoline|Eluxadoline]] is a peripherally restricted KOR agonist as well as MOR agonist and DOR antagonist that has been approved for the treatment of [[Medicine:Diarrhea|diarrhea]]-predominant [[Medicine:Irritable bowel syndrome|irritable bowel syndrome]]. [[Chemistry:Asimadoline|Asimadoline]] and [[Chemistry:Fedotozine|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 [[Chemistry:Diuretic|diuretic]] effects, due to their negative regulation of [[Biology:Vasopressin|vasopressin]], also known as antidiuretic hormone (ADH).<ref name="pmid2547626">{{cite journal | vauthors = Yamada K, Imai M, Yoshida S | title = Mechanism of diuretic action of U-62,066E, a kappa opioid receptor agonist | journal = European Journal of Pharmacology | volume = 160 | issue = 2 | pages = 229–37 | date = January 1989 | pmid = 2547626 | doi = 10.1016/0014-2999(89)90495-0 }}</ref>
* KOR agonism is neuroprotective against [[Medicine:Hypoxia (medical)|hypoxia]]/[[Medicine:Ischemia|ischemia]].<ref name="pmid16049424">{{cite journal | vauthors = Zeynalov E, Nemoto M, Hurn PD, Koehler RC, Bhardwaj A | title = Neuroprotective effect of selective kappa opioid receptor agonist is gender specific and linked to reduced neuronal nitric oxide | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 26 | issue = 3 | pages = 414–20 | date = March 2006 | pmid = 16049424 | doi = 10.1038/sj.jcbfm.9600196 | doi-access = free }}</ref>
* The selective KOR agonist [[Chemistry:U-50488|U-50488]] protected rats against supramaximal electroshock seizures, indicating that KOR agonism may have [[Chemistry:Anticonvulsant|anticonvulsant]] effects.<ref>{{cite journal | vauthors = Tortella FC, Robles L, Holaday JW | title = U50,488, a highly selective kappa opioid: anticonvulsant profile in rats | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 237 | issue = 1 | pages = 49–53 | date = April 1986 | pmid = 3007743 }}</ref>

== Signal transduction ==
KOR activation by agonists is coupled to the [[Biology:G protein|G protein]] [[Biology:Gi alpha subunit|G<sub>i</sub>/G<sub>0</sub>]], which subsequently increases [[Biology:Phosphodiesterase|phosphodiesterase]] activity. Phosphodiesterases break down [[Chemistry:Cyclic adenosine monophosphate|cAMP]], producing an inhibitory effect in neurons.<ref name="pmid8103800">{{cite journal | vauthors = Lawrence DM, Bidlack JM | title = The kappa opioid receptor expressed on the mouse R1.1 thymoma cell line is coupled to adenylyl cyclase through a pertussis toxin-sensitive guanine nucleotide-binding regulatory protein | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 266 | issue = 3 | pages = 1678–83 | date = September 1993 | pmid = 8103800 }}</ref><ref name="pmid8381004">{{cite journal | vauthors = Konkoy CS, Childers SR | title = Relationship between kappa 1 opioid receptor binding and inhibition of adenylyl cyclase in guinea pig brain membranes | journal = Biochemical Pharmacology | volume = 45 | issue = 1 | pages = 207–16 | date = January 1993 | pmid = 8381004 | doi = 10.1016/0006-2952(93)90394-C }}</ref><ref name="pmid2906610">{{cite journal | vauthors = Schoffelmeer AN, Rice KC, Jacobson AE, Van Gelderen JG, Hogenboom F, Heijna MH, Mulder AH | title = Mu-, delta- and kappa-opioid receptor-mediated inhibition of neurotransmitter release and adenylate cyclase activity in rat brain slices: studies with fentanyl isothiocyanate | journal = European Journal of Pharmacology | volume = 154 | issue = 2 | pages = 169–78 | date = September 1988 | pmid = 2906610 | doi = 10.1016/0014-2999(88)90094-5 | url = https://zenodo.org/record/1253868 }}</ref> KORs also couple to inward-rectifier potassium<ref name="pmid7700253">{{cite journal | vauthors = Henry DJ, Grandy DK, Lester HA, Davidson N, Chavkin C | title = Kappa-opioid receptors couple to inwardly rectifying potassium channels when coexpressed by Xenopus oocytes | journal = Molecular Pharmacology | volume = 47 | issue = 3 | pages = 551–7 | date = March 1995 | pmid = 7700253 }}</ref> and to [[Biology:N-type calcium channel|N-type calcium]] ion channels.<ref name="pmid7700508">{{cite journal | vauthors = Tallent M, Dichter MA, Bell GI, Reisine T | title = The cloned kappa opioid receptor couples to an N-type calcium current in undifferentiated PC-12 cells | journal = Neuroscience | volume = 63 | issue = 4 | pages = 1033–40 | date = December 1994 | pmid = 7700508 | doi = 10.1016/0306-4522(94)90570-3 | s2cid = 22003522 }}</ref> 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, [[Biology:P38 mitogen-activated protein kinases|p38 mitogen-activated protein kinases]], and [[Biology:C-Jun N-terminal kinases|c-Jun N-terminal kinases]].<ref name="pmid10646507">{{cite journal | vauthors = Bohn LM, Belcheva MM, Coscia CJ | title = 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 = Journal of Neurochemistry | volume = 74 | issue = 2 | pages = 564–73 | date = February 2000 | pmid = 10646507 | pmc = 2504523 | doi = 10.1046/j.1471-4159.2000.740564.x }}</ref><ref name="pmid15944153">{{cite journal | vauthors = Belcheva MM, Clark AL, Haas PD, Serna JS, Hahn JW, Kiss A, Coscia CJ | title = Mu and kappa opioid receptors activate ERK/MAPK via different protein kinase C isoforms and secondary messengers in astrocytes | journal = The Journal of Biological Chemistry | volume = 280 | issue = 30 | pages = 27662–9 | date = July 2005 | pmid = 15944153 | pmc = 1400585 | doi = 10.1074/jbc.M502593200 | doi-access = free }}</ref><ref name="pmid16648139">{{cite journal | vauthors = Bruchas MR, Macey TA, Lowe JD, Chavkin C | title = Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes | journal = The Journal of Biological Chemistry | volume = 281 | issue = 26 | pages = 18081–9 | date = June 2006 | pmid = 16648139 | pmc = 2096730 | doi = 10.1074/jbc.M513640200 | doi-access = free }}</ref><ref name="pmid18766023">{{cite journal | vauthors = Bruchas MR, Xu M, Chavkin C | title = Repeated swim stress induces kappa opioid-mediated activation of extracellular signal-regulated kinase 1/2 | journal = NeuroReport | volume = 19 | issue = 14 | pages = 1417–22 | date = September 2008 | pmid = 18766023 | pmc = 2641011 | doi = 10.1097/WNR.0b013e32830dd655 }}</ref><ref name="pmid14996948">{{cite journal | vauthors = Kam AY, Chan AS, Wong YH | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 310 | issue = 1 | pages = 301–10 | date = July 2004 | pmid = 14996948 | doi = 10.1124/jpet.104.065078 | s2cid = 39445016 }}</ref><ref name="pmid17702750">{{cite journal | vauthors = Bruchas MR, Yang T, Schreiber S, Defino M, Kwan SC, Li S, Chavkin C | title = Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase | journal = The Journal of Biological Chemistry | volume = 282 | issue = 41 | pages = 29803–11 | date = October 2007 | pmid = 17702750 | pmc = 2096775 | doi = 10.1074/jbc.M705540200 | doi-access = free }}</ref>

==Ligands==
[[File:22-Thiocyanatosalvinorin A.png|right|233px|thumb|22-Thiocyanatosalvinorin A (RB-64) is a [[Biology:Functional selectivity|functionally-selective]] κ-opioid receptor agonist.]]

=== Agonists ===
The synthetic alkaloid [[Chemistry:Ketazocine|ketazocine]]<ref name="pmid6251477">{{cite journal | vauthors = Pasternak GW | title = Multiple opiate receptors: [3H]ethylketocyclazocine receptor binding and ketocyclazocine analgesia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 77 | issue = 6 | pages = 3691–4 | date = June 1980 | pmid = 6251477 | pmc = 349684 | doi = 10.1073/pnas.77.6.3691 | bibcode = 1980PNAS...77.3691P | doi-access = free }}</ref> and terpenoid natural product [[Chemistry:Salvinorin A|salvinorin A]]<ref name="pmid12192085" /> are potent and selective KOR [[Biology:Agonist|agonist]]s. The KOR also mediates the [[Medicine:Dysphoria|dysphoria]] and [[Unsolved:Hallucination|hallucination]]s seen with opioids such as [[Chemistry:Pentazocine|pentazocine]].<ref name="pmid2859972">{{cite journal | vauthors = Holtzman SG | title = Drug discrimination studies | journal = Drug and Alcohol Dependence | volume = 14 | issue = 3–4 | pages = 263–82 | date = February 1985 | pmid = 2859972 | doi = 10.1016/0376-8716(85)90061-4 }}</ref>
{{div col|colwidth=20em}}
;Benzomorphans
* [[Chemistry:Alazocine|Alazocine]]– partial agonist
* [[Chemistry:Bremazocine|Bremazocine]] – highly selective
* [[Chemistry:8-Carboxamidocyclazocine|8-Carboxamidocyclazocine]]
* [[Chemistry:Cyclazocine|Cyclazocine]] – partial agonist
* [[Chemistry:Ketazocine|Ketazocine]]
* [[Chemistry:Metazocine|Metazocine]] – partial agonist
* [[Chemistry:Pentazocine|Pentazocine]] – partial agonist
* [[Chemistry:Phenazocine|Phenazocine]] – partial agonist

;[[Chemistry:Morphinan|Morphinan]]s
* [[Chemistry:6'-Guanidinonaltrindole|6'-Guanidinonaltrindole]] (6'-GNTI) – biased ligand: G protein agonist, β-arrestin antagonist
* Butorphan – full agonist
* [[Chemistry:Butorphanol|Butorphanol]] – partial agonist
* [[Chemistry:Cyclorphan|Cyclorphan]] – full agonist
* [[Chemistry:Diprenorphine|Diprenorphine]] – non-selective, partial agonist
* [[Chemistry:Etorphine|Etorphine]] – non-selective
* [[Chemistry:Levallorphan|Levallorphan]]
* [[Chemistry:Levomethorphan|Levomethorphan]]
* [[Chemistry:Levorphanol|Levorphanol]]
* [[Biology:Morphine|Morphine]] – alkaloid
* [[Chemistry:Nalbuphine|Nalbuphine]] – partial agonist
* [[Chemistry:Nalfurafine|Nalfurafine]] – full agonist, atypical agonist (possibly biased or subtype-selective)
* [[Chemistry:Nalmefene|Nalmefene]] – partial agonist
* [[Chemistry:Nalodeine|Nalodeine]]
* [[Chemistry:Nalorphine|Nalorphine]] – partial agonist
* [[Chemistry:Norbuprenorphine|Norbuprenorphine]] – partial agonist, peripherally-selective metabolite of buprenorphine
* [[Chemistry:Norbuprenorphine-3-glucuronide|Norbuprenorphine-3-glucuronide]] – likely partial agonist, peripherally-selective metabolite of buprenorphine
* [[Chemistry:Oxilorphan|Oxilorphan]] – partial agonist
* [[Chemistry:Oxycodone|Oxycodone]] – selective for κ<sub>2b</sub> subtype<ref name="pmid17467904">{{cite journal | vauthors = Nielsen CK, Ross FB, Lotfipour S, Saini KS, Edwards SR, Smith MT | title = Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain | journal = Pain | volume = 132 | issue = 3 | pages = 289–300 | date = December 2007 | pmid = 17467904 | doi = 10.1016/j.pain.2007.03.022 | s2cid = 19872213 }}</ref>
* [[Chemistry:Proxorphan|Proxorphan]] – partial agonist
* [[Chemistry:Samidorphan|Samidorphan]] – non-selective, weak partial agonist
* [[Chemistry:Xorphanol|Xorphanol]] – partial agonist

;[[Chemistry:Aryl|Aryl]][[Chemistry:Acetamide|acetamide]]s
* [[Chemistry:Asimadoline|Asimadoline]] – peripherally-selective
* [[Chemistry:BRL-52537|BRL-52537]]
* [[Chemistry:Eluxadoline|Eluxadoline]]
* [[Chemistry:Enadoline|Enadoline]]
* [[Chemistry:GR-89696|GR-89696]] – selective for κ<sub>2</sub>
* [[Chemistry:ICI-204,448|ICI-204,448]] – peripherally-selective
* [[Chemistry:ICI-199,441|ICI-199,441]]
* [[Chemistry:LPK-26|LPK-26]] – highly selective
* MB-1C-OH [https://www.ncbi.nlm.nih.gov/pubmed/25816912]
* [[Chemistry:Niravoline|Niravoline]]
* N-MPPP [https://www.ncbi.nlm.nih.gov/pubmed/8071934]
* [[Chemistry:Spiradoline|Spiradoline]]
* U-50,488
* U-54,494A [https://www.ncbi.nlm.nih.gov/pubmed/2824750]
* [[Chemistry:U-69,593|U-69,593]]

;[[Chemistry:Peptide|Peptide]]s (endo-/exogenous)
* [[Chemistry:CR665|CR665]] – peripherally-selective [http://www.caratherapeutics.com/cr845-other.shtml]
* [[Chemistry:Difelikefalin|Difelikefalin (CR845)]] – peripherally-selective [http://www.caratherapeutics.com/cr845.shtml]
* [[Biology:Dynorphin|Dynorphin]]s ([[Chemistry:Dynorphin A|dynorphin A]], [[Chemistry:Dynorphin B|dynorphin B]], [[Biology:Big dynorphin|big dynorphin]])

;[[Biology:Terpenoid|Terpenoid]]s
* [[Chemistry:Erinacine|Erinacine E]]
* [[Chemistry:Menthol|Menthol]]
* [[Chemistry:RB-64|RB-64]] – G protein biased agonist with a [[Biology:Functional selectivity|bias factor]] of 96; β-arrestin antagonist<ref name="pmid25320048">{{cite journal | vauthors = White KL, Robinson JE, Zhu H, DiBerto JF, Polepally PR, Zjawiony JK, Nichols DE, Malanga CJ, Roth BL | title = The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 352 | issue = 1 | pages = 98–109 | date = January 2015 | pmid = 25320048 | doi = 10.1124/jpet.114.216820 | pmc=4279099}}</ref>
* [[Chemistry:Salvinorin A|Salvinorin A]] – naturally-occurring
* [[Chemistry:Salvinorin B methoxymethyl ether|2-Methoxymethyl salvinorin B]]<ref name="pmid18089845">{{cite journal | vauthors = Wang Y, Chen Y, Xu W, Lee DY, Ma Z, Rawls SM, Cowan A, Liu-Chen LY | title = 2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 324 | issue = 3 | pages = 1073–83 | date = March 2008 | pmid = 18089845 | pmc = 2519046 | doi = 10.1124/jpet.107.132142 }}</ref> – and its ethoxymethyl and fluoroethoxymethyl homologues<ref name="pmid17981041">{{cite journal | vauthors = Munro TA, Duncan KK, Xu W, Wang Y, Liu-Chen LY, Carlezon WA, Cohen BM, Béguin C | title = Standard protecting groups create potent and selective kappa opioids: salvinorin B alkoxymethyl ethers | journal = Bioorganic & Medicinal Chemistry | volume = 16 | issue = 3 | pages = 1279–86 | date = February 2008 | pmid = 17981041 | pmc = 2568987 | doi = 10.1016/j.bmc.2007.10.067 }}</ref><ref name="pmid19153716">{{cite journal | vauthors = Baker LE, Panos JJ, Killinger BA, Peet MM, Bell LM, Haliw LA, Walker SL | title = Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats | journal = Psychopharmacology | volume = 203 | issue = 2 | pages = 203–11 | date = April 2009 | pmid = 19153716 | doi = 10.1007/s00213-008-1458-3 | doi-access = free }}</ref>

;Others/unsorted
* Apadoline
* [[Chemistry:HS665|HS665]] [https://www.ncbi.nlm.nih.gov/pubmed/23134120]
* [[Chemistry:HZ-2|HZ-2]]
* [[Biology:Ibogaine|Ibogaine]] – alkaloid
* [[Chemistry:Ketamine|Ketamine]] (weak)
* [[Chemistry:Noribogaine|Noribogaine]] – non-selective, biased ligand: G protein agonist, β-arrestin antagonist
* [[Chemistry:Tifluadom|Tifluadom]] – (atypical) benzodiazepine
* [[Chemistry:Mirtazapine|Mirtazapine]] - partial agonist at high concentrations 
* [[Chemistry:KSC-12-192|KSC-12-192]] - selective, biased ligand: G protein agonist, β-arrestin antagonist
{{Div col end}}

[[Chemistry:Nalfurafine|Nalfurafine]] (Remitch), which was introduced in 2009, is the first selective KOR agonist to enter clinical use.<ref name="Patrick2013">{{cite book| vauthors = Patrick GL |title=An Introduction to Medicinal Chemistry |url= https://books.google.com/books?id=Pj7xJRuhZxUC&pg=PA657 |date=10 January 2013|publisher=OUP Oxford |isbn=978-0-19-969739-7|pages=657–}}</ref><ref name="Nagase2011">{{cite book | vauthors = Nagase H |title= Chemistry of Opioids |url= https://books.google.com/books?id=eegLBwAAQBAJ&pg=PA34|date=21 January 2011 |publisher=Springer |isbn=978-3-642-18107-8 |pages=34, 48, 57–60}}</ref>

=== Antagonists ===
{{div col|colwidth=20em}}
* 5'-Acetamidinoethylnaltrindole (ANTI) – selective [https://www.ncbi.nlm.nih.gov/pubmed/10893314]
* [[Chemistry:5'-Guanidinonaltrindole|5'-Guanidinonaltrindole]] (5'-GNTI) – selective, long-acting
* [[Chemistry:6'-Guanidinonaltrindole|6'-Guanidinonaltrindole]] (6'-GNTI) – biased ligand: G protein agonist, β-arrestin antagonist
* [[Chemistry:Amentoflavone|Amentoflavone]] – non-selective; naturally-occurring<ref name="pmid17685652">{{cite journal | vauthors = Katavic PL, Lamb K, Navarro H, Prisinzano TE | title = Flavonoids as opioid receptor ligands: identification and preliminary structure-activity relationships | journal = Journal of Natural Products | volume = 70 | issue = 8 | pages = 1278–82 | date = August 2007 | pmid = 17685652 | pmc = 2265593 | doi = 10.1021/np070194x }}</ref>
* [[Chemistry:AT-076|AT-076]] – non-selective, likely long acting; JDTic analogue
* [[Chemistry:Aticaprant|Aticaprant]] – selective, short-acting
* [[Chemistry:Binaltorphimine|Binaltorphimine]] – selective, long-acting
* [[Chemistry:BTRX-335140|BTRX-335140]] - selective
* [[Chemistry:BU09059|BU09059]] – selective, short-acting; JDTic analogue<ref name="pmid24410326"/>
* [[Chemistry:Buprenorphine|Buprenorphine]] – non-selective; silent antagonist or weak partial agonist, depending on source
* [[Chemistry:CVL-354|CVL-354]] – selective, short-acting<ref>{{cite web|url=http://adisinsight.springer.com/drugs/800057691|title=CVL-354 | website=adisinsight.springer.com|access-date=2 February 2023}}</ref>
* [[Chemistry:Dezocine|Dezocine]] – non-selective; silent antagonist
* DIPPA – selective, long-acting [https://www.ncbi.nlm.nih.gov/pubmed/8201586]
* [[Chemistry:JDTic|JDTic]] – selective, long-acting
* [[Chemistry:LY-255582|LY-255582]] - non-selective
* [[Chemistry:LY-2459989|LY-2459989]] – selective, short-acting
* LY-2795050 – selective, short-acting
* [[Chemistry:Methylnaltrexone|Methylnaltrexone]] – non-selective
* ML190 – selective [https://www.ncbi.nlm.nih.gov/pubmed/22091479]
* ML350 – selective, short-acting<ref name="pmid24410326">{{cite journal | vauthors = Casal-Dominguez JJ, Furkert D, Ostovar M, Teintang L, Clark MJ, Traynor JR, Husbands SM, Bailey SJ | title = Characterization of BU09059: a novel potent selective κ-receptor antagonist | journal = ACS Chemical Neuroscience | volume = 5 | issue = 3 | pages = 177–84 | date = March 2014 | pmid = 24410326 | doi = 10.1021/cn4001507 | pmc=3963132}}</ref>
* MR-2266 – non-selective
* [[Chemistry:Naloxone|Naloxone]] – non-selective
* [[Chemistry:Naltrexone|Naltrexone]] – non-selective
* [[Chemistry:Noribogaine|Noribogaine]] – non-selective; naturally-occurring; biased ligand: G protein agonist, β-arrestin antagonist
* [[Chemistry:Norbinaltorphimine|Norbinaltorphimine]] – selective, long-acting
* [[Chemistry:Pawhuskin A|Pawhuskin A]] – selective; naturally-occurring<ref name="pmid24456556">{{cite journal | vauthors = Hartung AM, Beutler JA, Navarro HA, Wiemer DF, Neighbors JD | title = Stilbenes as κ-selective, non-nitrogenous opioid receptor antagonists | journal = Journal of Natural Products | volume = 77 | issue = 2 | pages = 311–9 | date = February 2014 | pmid = 24456556 | doi = 10.1021/np4009046 | pmc=3993902}}</ref>
* [[Chemistry:PF-4455242|PF-4455242]] – selective, short-acting
* [[Chemistry:Quadazocine|Quadazocine]] – non-selective; silent antagonist; preference for κ<sub>2</sub>
* [[Chemistry:RB-64|RB-64]] (22-thiocyanatosalvinorin A) – G protein biased agonist with a [[Biology:Functional selectivity|bias factor]] of 96; β-arrestin antagonist<ref name="pmid25320048"/>
* [[Chemistry:Zyklophin|Zyklophin]] – selective peptide antagonist; dynorphin A analogue
* [[Chemistry:KSC-12-192|KSC-12-192]] - selective, biased ligand: G protein agonist, β-arrestin antagonist
{{Div col end}}

=== Natural agonists ===

==== Mentha spp.==== 
{{Main|Chemistry:Menthol}}

Found in numerous species of mint, (including [[Biology:Peppermint|peppermint]], [[Biology:Spearmint|spearmint]], and watermint), the naturally-occurring compound [[Chemistry:Menthol|menthol]] is a weak KOR agonist<ref name="pmid11897159">{{cite journal | vauthors = Galeotti N, Di Cesare Mannelli L, Mazzanti G, Bartolini A, Ghelardini C | title = Menthol: a natural analgesic compound | journal = Neuroscience Letters | volume = 322 | issue = 3 | pages = 145–8 | date = April 2002 | pmid = 11897159 | doi = 10.1016/S0304-3940(01)02527-7 | s2cid = 33979563 }}</ref> owing to its antinociceptive, or pain blocking, effects in rats. In addition, mints can desensitize a region through the activation of [[Biology:TRPM8|TRPM8]] receptors (the 'cold'/menthol receptor).<ref name="pmid16945367">{{cite journal | vauthors = Werkheiser JL, Rawls SM, Cowan A | title = Mu and kappa opioid receptor agonists antagonize icilin-induced wet-dog shaking in rats | journal = European Journal of Pharmacology | volume = 547 | issue = 1–3 | pages = 101–5 | date = October 2006 | pmid = 16945367 | doi = 10.1016/j.ejphar.2006.07.026 }}</ref>

==== Salvia divinorum ====
{{Main|Biology:Salvia divinorum}}

The key compound in ''[[Biology:Salvia divinorum|Salvia divinorum]]'', [[Chemistry:Salvinorin A|salvinorin A]], is known as a powerful, short-acting KOR agonist.<ref name="pmid12192085" /><ref name="pmid17060493">{{cite journal | vauthors = Butelman ER, Mandau M, Tidgewell K, Prisinzano TE, Yuferov V, Kreek MJ | title = Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 320 | issue = 1 | pages = 300–6 | date = January 2007 | pmid = 17060493 | doi = 10.1124/jpet.106.112417 | s2cid = 5555012 | url = http://www.sagewisdom.org/butelmanetal2.pdf }}</ref><ref name="pmid14718611">{{cite journal | vauthors = Chavkin C, Sud S, Jin W, Stewart J, Zjawiony JK, Siebert DJ, Toth BA, Hufeisen SJ, Roth BL | title = Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 308 | issue = 3 | pages = 1197–203 | date = March 2004 | pmid = 14718611 | doi = 10.1124/jpet.103.059394 | s2cid = 2398097 }}</ref>

==== Ibogaine ====
{{Main|Biology:Ibogaine}}

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<ref name="pmid9668680">{{cite journal | vauthors = Glick SD, Maisonneuve IS | title = Mechanisms of antiaddictive actions of ibogaine | journal = Annals of the New York Academy of Sciences | volume = 844 | issue = 1 | pages = 214–226 | date = May 1998 | pmid = 9668680 | doi = 10.1111/j.1749-6632.1998.tb08237.x | s2cid = 11416176 | bibcode = 1998NYASA.844..214G }}</ref> and this property may contribute to the drug's anti-addictive efficacy.<ref>{{Cite journal | vauthors = Havel V, Kruegel AC, Bechand B, McIntosh S, Stallings L, Hodges A, Wulf MG, Nelson M, Hunkele A, Ansonoff M, Pintar JE, Hwu C, Abi-Gerges N, Zaidi SA, Katritch V | display-authors = 6 |date=2021-07-23 |title=Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Addiction States| journal = bioRxiv |language=en |pages=2021.07.22.453441 |doi=10.1101/2021.07.22.453441| s2cid = 236436956 }}</ref>

====''Mitragyna speciosa''====
{{Main|Biology:Mitragyna speciosa}}

==Role in treatment of drug addiction==
KOR agonists have been investigated for their therapeutic potential in the treatment of addiction<ref name="pmid15542743">{{cite journal | vauthors = Hasebe K, Kawai K, Suzuki T, Kawamura K, Tanaka T, Narita M, Nagase H, Suzuki T | title = Possible pharmacotherapy of the opioid kappa receptor agonist for drug dependence | journal = Annals of the New York Academy of Sciences | volume = 1025 | pages = 404–13 | date = October 2004 | issue = 1 | pmid = 15542743 | doi = 10.1196/annals.1316.050 | bibcode = 2004NYASA1025..404H | s2cid = 85031737 }}</ref> and evidence points towards [[Biology:Dynorphin|dynorphin]], the endogenous KOR agonist, to be the body's natural addiction control mechanism.<ref name="pmid18538358">{{cite journal | vauthors = Frankel PS, Alburges ME, Bush L, Hanson GR, Kish SJ | title = Striatal and ventral pallidum dynorphin concentrations are markedly increased in human chronic cocaine users | journal = Neuropharmacology | volume = 55 | issue = 1 | pages = 41–6 | date = July 2008 | pmid = 18538358 | pmc = 2577569 | doi = 10.1016/j.neuropharm.2008.04.019 }}</ref> Childhood stress/abuse is a well known predictor of drug abuse and is reflected in alterations of the MOR and KOR systems.<ref name="pmid18203949">{{cite journal | vauthors = Michaels CC, Holtzman SG | title = Early postnatal stress alters place conditioning to both mu- and kappa-opioid agonists | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 325 | issue = 1 | pages = 313–8 | date = April 2008 | pmid = 18203949 | doi = 10.1124/jpet.107.129908 | s2cid = 30383220 }}</ref> 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.<ref name="pmid16184376">{{cite journal | vauthors = Beardsley PM, Howard JL, Shelton KL, Carroll FI | title = 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 | journal = Psychopharmacology | volume = 183 | issue = 1 | pages = 118–26 | date = November 2005 | pmid = 16184376 | doi = 10.1007/s00213-005-0167-4 | s2cid = 31140425 }}</ref><ref name="pmid18575850">{{cite journal | vauthors = Redila VA, Chavkin C | title = Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system | journal = Psychopharmacology | volume = 200 | issue = 1 | pages = 59–70 | date = September 2008 | pmid = 18575850 | pmc = 2680147 | doi = 10.1007/s00213-008-1122-y }}</ref>

One area of the brain most strongly associated with addiction is the [[Biology:Nucleus accumbens|nucleus accumbens]] (NAcc) and [[Biology:Striatum|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 [[Biology:Dopamine receptor D2|dopamine D<sub>2</sub> receptors]] in the NAcc.<ref name="pmid11280926">{{cite journal | vauthors = Blum K, Braverman ER, Holder JM, Lubar JF, Monastra VJ, Miller D, Lubar JO, Chen TJ, Comings DE | title = Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors | journal = Journal of Psychoactive Drugs | volume = 32 | issue = Suppl | pages = i-iv, 1–112 | date = November 2000 | pmid = 11280926 | doi = 10.1080/02791072.2000.10736099 | s2cid = 22497665 }}</ref> In addition to low NAcc D<sub>2</sub> binding,<ref name="pmid17544385">{{cite journal | vauthors = Stefański R, Ziółkowska B, Kuśmider M, Mierzejewski P, Wyszogrodzka E, Kołomańska P, Dziedzicka-Wasylewska M, Przewłocki R, Kostowski W | title = Active versus passive cocaine administration: differences in the neuroadaptive changes in the brain dopaminergic system | journal = Brain Research | volume = 1157 | pages = 1–10 | date = July 2007 | pmid = 17544385 | doi = 10.1016/j.brainres.2007.04.074 | s2cid = 42090922 }}</ref><ref name="pmid9704885">{{cite journal | vauthors = Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP | title = Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys | journal = Synapse | volume = 30 | issue = 1 | pages = 88–96 | date = September 1998 | pmid = 9704885 | doi = 10.1002/(SICI)1098-2396(199809)30:1<88::AID-SYN11>3.0.CO;2-L | s2cid = 22569502 | doi-access = free }}</ref> 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 [[Biology:Hypothalamus|hypothalamus]] while the administration of a KOR agonist produced an opposite effect causing an increase in D<sub>2</sub> receptors in the NAcc.<ref name="pmid17055175">{{cite journal | vauthors = D'Addario C, Di Benedetto M, Izenwasser S, Candeletti S, Romualdi P | title = Role of serotonin in the regulation of the dynorphinergic system by a kappa-opioid agonist and cocaine treatment in rat CNS | journal = Neuroscience | volume = 144 | issue = 1 | pages = 157–64 | date = January 2007 | pmid = 17055175 | doi = 10.1016/j.neuroscience.2006.09.008 | s2cid = 34243587 }}</ref>

Additionally, while cocaine overdose victims showed a large increase in KORs (doubled) in the NAcc,<ref name="pmid10415668">{{cite journal | vauthors = Mash DC, Staley JK | title = D3 dopamine and kappa opioid receptor alterations in human brain of cocaine-overdose victims | journal = Annals of the New York Academy of Sciences | volume = 877 | issue =  1| pages = 507–22 | date = June 1999 | pmid = 10415668 | doi = 10.1111/j.1749-6632.1999.tb09286.x | bibcode = 1999NYASA.877..507M | s2cid = 25867468 }}</ref> KOR agonist administration is shown to be effective in decreasing cocaine seeking and self-administration.<ref name="pmid10435406">{{cite journal | vauthors = Schenk S, Partridge B, Shippenberg TS | title = U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking | journal = Psychopharmacology | volume = 144 | issue = 4 | pages = 339–46 | date = June 1999 | pmid = 10435406 | doi = 10.1007/s002130051016 | s2cid = 19726351 }}</ref> Furthermore, while cocaine abuse is associated with lowered prolactin response,<ref name="pmid16915581">{{cite journal | vauthors = Patkar AA, Mannelli P, Hill KP, Peindl K, Pae CU, Lee TH | title = Relationship of prolactin response to meta-chlorophenylpiperazine with severity of drug use in cocaine dependence | journal = Human Psychopharmacology | volume = 21 | issue = 6 | pages = 367–75 | date = August 2006 | pmid = 16915581 | doi = 10.1002/hup.780 | s2cid = 21895907 | doi-access = free }}</ref> KOR activation causes a release in [[Biology:Prolactin|prolactin]],<ref name="pmid11448491">{{cite journal | vauthors = Butelman ER, Kreek MJ | title = kappa-Opioid receptor agonist-induced prolactin release in primates is blocked by dopamine D(2)-like receptor agonists | journal = European Journal of Pharmacology | volume = 423 | issue = 2–3 | pages = 243–9 | date = July 2001 | pmid = 11448491 | doi = 10.1016/S0014-2999(01)01121-9 }}</ref> a hormone known for its important role in learning, neuronal plasticity and myelination.<ref name="pmid17314279">{{cite journal | vauthors = Gregg C, Shikar V, Larsen P, Mak G, Chojnacki A, Yong VW, Weiss S | title = White matter plasticity and enhanced remyelination in the maternal CNS | journal = The Journal of Neuroscience | volume = 27 | issue = 8 | pages = 1812–23 | date = February 2007 | pmid = 17314279 | doi = 10.1523/JNEUROSCI.4441-06.2007 | pmc = 6673564 }}</ref>

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.<ref name="pmid12843270">{{cite journal | vauthors = McLaughlin JP, Marton-Popovici M, Chavkin C | title = Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses | journal = The Journal of Neuroscience | volume = 23 | issue = 13 | pages = 5674–83 | date = July 2003 | pmid = 12843270 | pmc = 2104777 | doi =  10.1523/JNEUROSCI.23-13-05674.2003}}</ref><ref name="pmid16123746">{{cite journal | vauthors = McLaughlin JP, Li S, Valdez J, Chavkin TA, Chavkin C | title = Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system | journal = Neuropsychopharmacology | volume = 31 | issue = 6 | pages = 1241–8 | date = June 2006 | pmid = 16123746 | pmc = 2096774 | doi = 10.1038/sj.npp.1300872 }}</ref> 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|homeostasis]] to [[Biology:Allostasis|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.<ref name="pmid18614026">{{cite journal | vauthors = Koob GF | title = A role for brain stress systems in addiction | journal = Neuron | volume = 59 | issue = 1 | pages = 11–34 | date = July 2008 | pmid = 18614026 | pmc = 2748830 | doi = 10.1016/j.neuron.2008.06.012 }}</ref> 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.<ref name="pmid18766023"/><ref name=Bruchas>{{cite journal | vauthors = Bruchas MR, Land BB, Aita M, Xu M, Barot SK, Li S, Chavkin C | title = Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria | journal = The Journal of Neuroscience | volume = 27 | issue = 43 | pages = 11614–23 | date = October 2007 | pmid = 17959804 | pmc = 2481272 | doi = 10.1523/JNEUROSCI.3769-07.2007 }}</ref>

While the predominant drugs of abuse examined have been cocaine (44%), ethanol (35%), and opioids (24%).<ref name="pmid31463605">{{cite book | vauthors = Banks ML | title = Substance Use Disorders | chapter = The Rise and Fall of Kappa-Opioid Receptors in Drug Abuse Research | series = Handbook of Experimental Pharmacology | volume = 258 | pages = 147–165 | date = 2020 | pmid = 31463605 | doi = 10.1007/164_2019_268 | isbn = 978-3-030-33678-3 | pmc = 7756963 }}</ref> As these are different classes of drugs of abuse working through different receptors (increasing dopamine directly and indirectly, respectively) albeit in the same systems produce functionally different responses. Conceptually then pharmacological activation of KOR can have marked effects in any of the psychiatric disorders (depression, bipolar disorder, anxiety, etc.) as well as various neurological disorders (i.e. Parkinson's disease and Huntington's disease).<ref name="Karkhanis_2017"/><ref name="pmid30244022"/> 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.<ref name="pmid16001119">{{cite journal | vauthors = Mitchell JM, Liang MT, Fields HL | title = A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats | journal = Psychopharmacology | volume = 182 | issue = 3 | pages = 384–92 | date = November 2005 | pmid = 16001119 | doi = 10.1007/s00213-005-0067-7 | s2cid = 38011973 }}</ref> There are numerous studies that reflect a reduction in self-administration of alcohol,<ref name="pmid17473837">{{cite journal | vauthors = Walker BM, Koob GF | title = Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence | journal = Neuropsychopharmacology | volume = 33 | issue = 3 | pages = 643–52 | date = February 2008 | pmid = 17473837 | pmc = 2739278 | doi = 10.1038/sj.npp.1301438 }}</ref> and heroin dependence has also been shown to be effectively treated with KOR agonism by reducing the immediate rewarding effects<ref name="pmid9435173">{{cite journal | vauthors = Xi ZX, Fuller SA, Stein EA | title = Dopamine release in the nucleus accumbens during heroin self-administration is modulated by kappa opioid receptors: an in vivo fast-cyclic voltammetry study | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 284 | issue = 1 | pages = 151–61 | date = January 1998 | pmid = 9435173 }}</ref> and by causing the curative effect of up-regulation (increased production) of MORs<ref name="pmid12753076">{{cite journal | vauthors = Narita M, Khotib J, Suzuki M, Ozaki S, Yajima Y, Suzuki T | title = Heterologous mu-opioid receptor adaptation by repeated stimulation of kappa-opioid receptor: up-regulation of G-protein activation and antinociception | journal = Journal of Neurochemistry | volume = 85 | issue = 5 | pages = 1171–9 | date = June 2003 | pmid = 12753076 | doi = 10.1046/j.1471-4159.2003.01754.x | s2cid = 26034314 }}</ref> 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<ref name="pmid7898771">{{cite journal | vauthors = Maisonneuve IM, Archer S, Glick SD | title = U50,488, a kappa opioid receptor agonist, attenuates cocaine-induced increases in extracellular dopamine in the nucleus accumbens of rats | journal = Neuroscience Letters | volume = 181 | issue = 1–2 | pages = 57–60 | date = November 1994 | pmid = 7898771 | doi = 10.1016/0304-3940(94)90559-2 | s2cid = 25258989 }}</ref> and over the long term up-regulates receptors that have been down-regulated during substance abuse such as the MOR and the D<sub>2</sub> receptor. These receptors modulate the release of other [[Biology:Neurochemical|neurochemical]]s such as [[Chemistry:Serotonin|serotonin]] in the case of MOR agonists and acetylcholine in the case of D<sub>2</sub>. 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 [[Biology:Dopamine|dopamine]], [[Chemistry:Serotonin|serotonin]], or [[Biology:Norepinephrine|norepinephrine]] and/or via activation of downstream signal transduction pathways.

Of significant note, while KOR activation blocks many of the behavioral and neurochemical responses elicited by drugs of abuse as stated above. These results are indicative of the KOR induced negative affective states counteracting the rewarding effects of drugs of abuse. Implicating the KOR/dynorphin system as an anti-reward system, supported by the role of KOR signaling and stress, mediating both stress-induced potentiation of drug reward and stress-induced reinstatement of seeking behavior.<ref name="Karkhanis_2017"/><ref name="pmid30244022">{{cite journal | vauthors = Tejeda HA, Bonci A | title = Dynorphin/kappa-opioid receptor control of dopamine dynamics: Implications for negative affective states and psychiatric disorders | journal = Brain Research | volume = 1713 | pages = 91–101 | date = June 2019 | pmid = 30244022 | doi = 10.1016/j.brainres.2018.09.023 | s2cid = 52339964 }}</ref> This in turn addresses what was thought to be paradoxical above. That is, rather, KOR signaling is activated/upregulated by stress, drugs of abuse and agonist administration - resulting in negative affective state. As such drug addiction is maintained by avoidance of negative affective states manifest in stress, craving, and drug withdrawal.<ref name="pmid20352414">{{cite journal | vauthors = Wee S, Koob GF | title = The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse | journal = Psychopharmacology | volume = 210 | issue = 2 | pages = 121–35 | date = June 2010 | pmid = 20352414 | doi = 10.1007/s00213-010-1825-8 | pmc = 2879894 }}</ref> Consistent with KOR induced negative affective states and role in drug addiction, KOR antagonists are efficacious at blocking negative affect induced by drug withdrawal and at decreasing escalated drug intake in pre-clinical trial involving extended drug access.<ref name="Karkhanis_2017"/><ref name="pmid30244022"/><ref name="pmid31463605"/> Clinically there has been little advancement to evaluate the effects of KOR antagonists due to adverse effects and undesirable pharmacological profiles for clinical testing (i.e. long half-life, poor bioavailability). More recently, a selective, high-affinity KOR antagonist LY2456302 was well-tolerated in CUD patients.<ref name="pmid29422497">{{cite journal | vauthors = Reed B, Butelman ER, Fry RS, Kimani R, Kreek MJ | title = Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence | journal = Neuropsychopharmacology | volume = 43 | issue = 4 | pages = 928 | date = March 2018 | pmid = 29422497 | doi = 10.1038/npp.2017.245 | pmc = 5809793 | doi-access = free }}</ref> Showing feasibility a subsequent proof-of-mechanism trial evaluated [[Chemistry:Aticaprant|JNJ-67953964]] (previously LY2456302) potential for treating anhedonia in a double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder.<ref name="pmid32231295">{{cite journal | vauthors = Krystal AD, Pizzagalli DA, Smoski M, Mathew SJ, Nurnberger J, Lisanby SH, Iosifescu D, Murrough JW, Yang H, Weiner RD, Calabrese JR, Sanacora G, Hermes G, Keefe RS, Song A, Goodman W, Szabo ST, Whitton AE, Gao K, Potter WZ | display-authors = 6 | title = A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia | journal = Nature Medicine | volume = 26 | issue = 5 | pages = 760–768 | date = May 2020 | pmid = 32231295 | doi = 10.1038/s41591-020-0806-7 | pmc = 9949770 | s2cid = 214704502 }}</ref> The KOR antagonist significantly increased fMRI ventral striatum activation during reward anticipation while accompanied by therapeutic effects on clinical measures of anhedonia, further reinforces the promise of KOR antagonism and proceeding assessment of clinical impact.<ref name="pmid32231295"/> Additionally a positron emission tomography (PET) study in cocaine use disorder (CUD) patients utilizing a KOR selective agonist [<sup>11</sup>C]GR103545 radioligand showed CUD individuals with higher KOR availability were more prone to stress-induced relapse.<ref name="pmid31026862"/> A subsequent PET scan following a three-day cocaine binge showed a decrease in KOR availability, interpreted as increased endogenous dynorphin competing with the radioligand at the KOR binding sites.<ref name="pmid31026862">{{cite journal | vauthors = Martinez D, Slifstein M, Matuskey D, Nabulsi N, Zheng MQ, Lin SF, Ropchan J, Urban N, Grassetti A, Chang D, Salling M, Foltin R, Carson RE, Huang Y | display-authors = 6 | title = Kappa-opioid receptors, dynorphin, and cocaine addiction: a positron emission tomography study | journal = Neuropsychopharmacology | volume = 44 | issue = 10 | pages = 1720–1727 | date = September 2019 | pmid = 31026862 | doi = 10.1038/s41386-019-0398-4 | pmc = 6785004 }}</ref> Taken together these findings are in support of the negative affect state and further implicate the KOR/dynorphin system clinically and therapeutically relevant in humans with CUD. 
Taken together, in drug addiction the KOR/dynorphin system is implicated as a homeostatic mechanism to counteract the acute effects of drugs of abuse. Chronic drug use and stress up-regulate the system in turn leading to a dysregulated state which induces negative affective states and stress reactivity.<ref name="pmid30244022"/>

Traditional models of KOR function in drug addiction have postulated that KOR signaling is associated with dysphoria and aversion, thought to underlie the stress-induced exacerbation of addiction. However, recent research in animal models has proposed alternative models, suggesting that KOR-mediated responses may not act directly on negative valence systems but modulate related processes such as novelty processing.<ref>{{cite journal | vauthors = Farahbakhsh ZZ, Song K, Branthwaite HE, Erickson KR, Mukerjee S, Nolan SO, Siciliano CA | title = Systemic kappa opioid receptor antagonism accelerates reinforcement learning via augmentation of novelty processing in male mice | journal = Neuropsychopharmacology | volume = 48 | issue = 6 | pages = 857–868 | date = May 2023 | pmid = 36804487 | doi = 10.1038/s41386-023-01547-x | pmc = 10156709 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Braden K, Castro DC | title = Kappa opioid receptors as modulators of novelty processing | journal = Neuropsychopharmacology | volume = 48 | issue = 6 | pages = 848–849 | date = May 2023 | pmid = 36922627 | doi = 10.1038/s41386-023-01561-z | pmc = 10156680 | doi-access = free | pmc-embargo-date = May 1, 2024 }}</ref> Studies in humans same to similar conclusions that KORs may modulate various aspects of reward processing in a manner that is independent of the hedonic valence traditionally ascribed to them.<ref>{{cite journal | vauthors = Pizzagalli DA, Smoski M, Ang YS, Whitton AE, Sanacora G, Mathew SJ, Nurnberger J, Lisanby SH, Iosifescu DV, Murrough JW, Yang H, Weiner RD, Calabrese JR, Goodman W, Potter WZ, Krystal AD | display-authors = 6 | title = Selective kappa-opioid antagonism ameliorates anhedonic behavior: evidence from the Fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS) | journal = Neuropsychopharmacology | volume = 45 | issue = 10 | pages = 1656–1663 | date = September 2020 | pmid = 32544925 | doi = 10.1038/s41386-020-0738-4 | pmc = 7419512 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Krystal AD, Pizzagalli DA, Smoski M, Mathew SJ, Nurnberger J, Lisanby SH, Iosifescu D, Murrough JW, Yang H, Weiner RD, Calabrese JR, Sanacora G, Hermes G, Keefe RS, Song A, Goodman W, Szabo ST, Whitton AE, Gao K, Potter WZ | display-authors = 6 | title = A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia | journal = Nature Medicine | volume = 26 | issue = 5 | pages = 760–768 | date = May 2020 | pmid = 32231295 | doi = 10.1038/s41591-020-0806-7 | pmc = 9949770 }}</ref> This broadens the potential understanding of KORs in addiction beyond a unidimensional framework, implicating their role in complex behaviors and treatment approaches that do not align strictly with stress or aversion. These emerging perspectives may inform the development of novel pharmacotherapies targeting KORs for the treatment of substance use disorders, as they highlight the receptor's multifaceted role in addiction.

== Interactions ==

KOR has been shown to interact with [[Biology:Sodium-hydrogen antiporter 3 regulator 1|sodium-hydrogen antiporter 3 regulator 1]],<ref name="pmid15070904">{{cite journal | vauthors = Huang P, Steplock D, Weinman EJ, Hall RA, Ding Z, Li J, Wang Y, Liu-Chen LY | title = 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 | journal = The Journal of Biological Chemistry | volume = 279 | issue = 24 | pages = 25002–9 | date = June 2004 | pmid = 15070904 | doi = 10.1074/jbc.M313366200 | doi-access = free }}</ref><ref name="pmid12004055">{{cite journal | vauthors = Li JG, Chen C, Liu-Chen LY | title = 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 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 30 | pages = 27545–52 | date = July 2002 | pmid = 12004055 | doi = 10.1074/jbc.M200058200 | doi-access = free }}</ref> [[Biology:Ubiquitin C|ubiquitin C]],<ref name="pmid18212250">{{cite journal | vauthors = Li JG, Haines DS, Liu-Chen LY | title = Agonist-promoted Lys63-linked polyubiquitination of the human kappa-opioid receptor is involved in receptor down-regulation | journal = Molecular Pharmacology | volume = 73 | issue = 4 | pages = 1319–30 | date = April 2008 | pmid = 18212250 | pmc = 3489932 | doi = 10.1124/mol.107.042846 }}</ref> [[Biology:5-HT1A receptor|5-HT1A receptor]],<ref>{{cite journal | vauthors = Maraschin JC, Almeida CB, Rangel MP, Roncon CM, Sestile CC, Zangrossi H, Graeff FG, Audi EA | title = Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the κ-opioid receptor antagonist Nor-BNI | journal = Behavioural Brain Research | volume = 327 | pages = 75–82 | date = June 2017 | pmid = 28347824 | doi = 10.1016/j.bbr.2017.03.033 | s2cid = 22465963 }}</ref> and RGS12.<ref>{{cite journal | vauthors = Gross JD, Kaski SW, Schmidt KT, Cogan ES, Boyt KM, Wix K, Schroer AB, McElligott ZA, Siderovski DP, Setola V | display-authors = 6 | title = Role of RGS12 in the differential regulation of kappa opioid receptor-dependent signaling and behavior | journal = Neuropsychopharmacology | volume = 44 | issue = 10 | pages = 1728–1741 | date = September 2019 | pmid = 31141817 | pmc = 6785087 | doi = 10.1038/s41386-019-0423-7 }}</ref>

== See also ==
* δ-opioid receptor
* μ-opioid receptor
* [[Biology:Nociceptin receptor|Nociceptin receptor]]

== References ==
{{Reflist|2}}

== External links ==
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2409 | title = Opioid Receptors: κ | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology }}
* {{MeshName|kappa+Opioid+Receptor}}

{{G protein-coupled receptors}}
{{Neuropeptide receptors}}
{{Opioidergics}}

{{DEFAULTSORT:Kappa Opioid Receptor}}
[[Category:Opioid receptors]]
[[Category:Kappa-opioid receptor agonists]]

{{Sourceattribution|Κ-opioid receptor}}