κ-opioid receptor
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| Location (UCSC) | Chr 8: 53.23 – 53.25 Mb | Chr 1: 5.66 – 5.68 Mb | |||||||
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The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.[5][6]
The KOR is a type of
There is evidence that distribution and/or function of this receptor may differ between sexes.[8][9][10][11]
Distribution
KORs are widely distributed in the
Subtypes
Based on receptor binding studies, three variants of the KOR designated κ1, κ2, and κ3 have been characterized.[14][15] However, only one cDNA clone has been identified,[16] hence these receptor subtypes likely arise from interaction of one KOR protein with other membrane associated proteins.[17]
Function
Pain
Similarly to
Consciousness
Centrally active KOR agonists have
The claustrum is the region of the brain in which the KOR is most densely expressed.[20][21][22] 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.[21][22] 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.[22][23] 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.[21][22] 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.[21] 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]".[22]
In supplementation of the above, according to Addy et al.:[20]
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.[20]
Mood, stress, and addiction
The involvement of the KOR in
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.[26] As such, KOR antagonists might be useful for the treatment of depressive symptoms associated with opioid withdrawal.[26]
In a small clinical study,
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 respiratory depression.[28]
- KOR agonists suppress itching, and the selective KOR agonist nalfurafine is used clinically as an antipruritic(anti-itch drug).
- 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).[29]
- KOR agonism is
- The selective KOR agonist seizures, indicating that KOR agonism may have anticonvulsant effects.[31]
Signal transduction
KOR activation by agonists is coupled to the
Ligands
Agonists
The synthetic alkaloid
- Alazocine– partial agonist
- Bremazocine – highly selective
- 8-Carboxamidocyclazocine
- Cyclazocine – partial agonist
- Ketazocine
- Metazocine – partial agonist
- Pentazocine – partial agonist
- Phenazocine – partial agonist
- 6'-Guanidinonaltrindole (6'-GNTI) – biased ligand: G protein agonist, β-arrestin antagonist
- Butorphan– full agonist
- Butorphanol – partial agonist
- Cyclorphan – full agonist
- Diprenorphine – non-selective, partial agonist
- Etorphine – non-selective
- Levallorphan
- Levomethorphan
- Levorphanol
- Morphine – alkaloid
- Nalbuphine – partial agonist
- Nalfurafine – full agonist, atypical agonist (possibly biased or subtype-selective)
- Nalmefene – partial agonist
- Nalodeine
- Nalorphine – partial agonist
- Norbuprenorphine – partial agonist, peripherally-selective metabolite of buprenorphine
- Norbuprenorphine-3-glucuronide – likely partial agonist, peripherally-selective metabolite of buprenorphine
- Oxilorphan – partial agonist
- Oxycodone – selective for κ2b subtype[45]
- Proxorphan – partial agonist
- Samidorphan – non-selective, weak partial agonist
- Xorphanol – partial agonist
- Arylacetamides
- Asimadoline – peripherally-selective
- BRL-52537
- Eluxadoline
- Enadoline
- GR-89696 – selective for κ2
- ICI-204,448 – peripherally-selective
- ICI-199,441
- LPK-26 – highly selective
- MB-1C-OH [1]
- Niravoline
- N-MPPP [2]
- Spiradoline
- U-50,488
- U-54,494A [3]
- U-69,593
- Peptides (endo-/exogenous)
- CR665 – peripherally-selective [4]
- Difelikefalin (CR845) – peripherally-selective [5]
- Dynorphins (dynorphin A, dynorphin B, big dynorphin)
- Erinacine E
- Menthol
- biased agonist with a bias factor of 96; β-arrestin antagonist[46]
- Salvinorin A – naturally-occurring
- Others/unsorted
- Apadoline
- HS665 [6]
- HZ-2
- Ibogaine – alkaloid
- Ketamine (weak)
- Noribogaine – non-selective, biased ligand: G protein agonist, β-arrestin antagonist
- Tifluadom – (atypical) benzodiazepine
- Mirtazapine - partial agonist at high concentrations
- KSC-12-192 - selective, biased ligand: G protein agonist, β-arrestin antagonist
Nalfurafine (Remitch), which was introduced in 2009, is the first selective KOR agonist to enter clinical use.[50][51]
Antagonists
- 5'-Acetamidinoethylnaltrindole (ANTI) – selective [7]
- 5'-Guanidinonaltrindole (5'-GNTI) – selective, long-acting
- 6'-Guanidinonaltrindole (6'-GNTI) – biased ligand: G protein agonist, β-arrestin antagonist
- Amentoflavone – non-selective; naturally-occurring[52]
- AT-076 – non-selective, likely long acting; JDTic analogue
- Aticaprant – selective, short-acting
- Binaltorphimine – selective, long-acting
- BU09059 – selective, short-acting; JDTic analogue[53]
- Buprenorphine – non-selective; silent antagonist or weak partial agonist, depending on source
- CVL-354 – selective, short-acting[54]
- Dezocine – non-selective; silent antagonist
- DIPPA – selective, long-acting [8]
- JDTic – selective, long-acting
- LY-255582 - non-selective
- LY-2459989 – selective, short-acting
- LY-2795050 – selective, short-acting
- Methylnaltrexone – non-selective
- ML190 – selective [9]
- ML350 – selective, short-acting[53]
- MR-2266 – non-selective
- Naloxone – non-selective
- Naltrexone – non-selective
- Navacaprant - selective
- Noribogaine – non-selective; naturally-occurring; biased ligand: G protein agonist, β-arrestin antagonist
- Norbinaltorphimine – selective, long-acting
- Pawhuskin A – selective; naturally-occurring[55]
- PF-4455242 – selective, short-acting
- Quadazocine – non-selective; silent antagonist; preference for κ2
- biased agonist with a bias factor of 96; β-arrestin antagonist[46]
- Zyklophin – selective peptide antagonist; dynorphin A analogue
- KSC-12-192 - selective, biased ligand: G protein agonist, β-arrestin antagonist
Natural agonists
Mentha spp.
Found in numerous species of mint, (including
Salvia divinorum
The key compound in Salvia divinorum, salvinorin A, is known as a powerful, short-acting KOR agonist.[19][58][59]
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
Mitragyna speciosa
Role in treatment of drug addiction
KOR agonists have been investigated for their therapeutic potential in the treatment of addiction[62] and evidence points towards dynorphin, the endogenous KOR agonist, to be the body's natural addiction control mechanism.[63] Childhood stress/abuse is a well known predictor of drug abuse and is reflected in alterations of the MOR and KOR systems.[64] 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.[65][66]
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.[67] In addition to low NAcc D2 binding,[68][69] 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.[70]
Additionally, while cocaine overdose victims showed a large increase in KORs (doubled) in the NAcc,[71] KOR agonist administration is shown to be effective in decreasing cocaine seeking and self-administration.[72] Furthermore, while cocaine abuse is associated with lowered prolactin response,[73] KOR activation causes a release in prolactin,[74] a hormone known for its important role in learning, neuronal plasticity and myelination.[75]
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.[76][77] 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.[78] 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.[40][79]
While the predominant drugs of abuse examined have been cocaine (44%), ethanol (35%), and opioids (24%).[80] 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).[6][81] 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.[82] There are numerous studies that reflect a reduction in self-administration of alcohol,[83] and heroin dependence has also been shown to be effectively treated with KOR agonism by reducing the immediate rewarding effects[84] and by causing the curative effect of up-regulation (increased production) of MORs[85] 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[86] 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.
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.
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.[91][92] 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.[93][94] 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
See also
- δ-opioid receptor
- μ-opioid receptor
- Nociceptin receptor
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000082556 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025905 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 28425121.
- ^ PMID 29056156.
- PMID 6128656.
- ^ PMID 26733781.
- PMID 20951148.
- PMID 26892380.
- PMID 36100655.
- PMID 20729876.
- S2CID 300974.
- PMID 2536435.
- PMID 2553442.
- PMID 8060324.
- PMID 10385123.
- ^ PMID 18184783.
- ^ PMID 12192085.
- ^ S2CID 34171297.
- ^ PMID 24624064.
- ^ S2CID 46139982.
- S2CID 8368944.
- PMID 16924269.
- ^ PMID 24690494.
- ^ S2CID 32817749.
- PMID 9584625.
- ISBN 978-1-4939-1951-2.
- PMID 2547626.
- PMID 16049424.
- PMID 3007743.
- PMID 8103800.
- PMID 8381004.
- PMID 2906610.
- PMID 7700253.
- S2CID 22003522.
- PMID 10646507.
- PMID 15944153.
- PMID 16648139.
- ^ PMID 18766023.
- S2CID 39445016.
- PMID 17702750.
- PMID 6251477.
- PMID 2859972.
- S2CID 19872213.
- ^ PMID 25320048.
- PMID 18089845.
- PMID 17981041.
- PMID 19153716.
- ISBN 978-0-19-969739-7.
- ISBN 978-3-642-18107-8.
- PMID 17685652.
- ^ PMID 24410326.
- ^ "CVL-354". adisinsight.springer.com. Retrieved 2 February 2023.
- PMID 24456556.
- S2CID 33979563.
- PMID 16945367.
- S2CID 5555012.
- S2CID 2398097.
- S2CID 11416176.
- S2CID 236436956.
- S2CID 85031737.
- PMID 18538358.
- S2CID 30383220.
- S2CID 31140425.
- PMID 18575850.
- S2CID 22497665.
- S2CID 42090922.
- S2CID 22569502.
- S2CID 34243587.
- S2CID 25867468.
- S2CID 19726351.
- S2CID 21895907.
- PMID 11448491.
- PMID 17314279.
- PMID 12843270.
- PMID 16123746.
- PMID 18614026.
- PMID 17959804.
- ^ PMID 31463605.
- ^ S2CID 52339964.
- S2CID 38011973.
- PMID 17473837.
- PMID 9435173.
- S2CID 26034314.
- S2CID 25258989.
- PMID 20352414.
- PMID 29422497.
- ^ S2CID 214704502.
- ^ PMID 31026862.
- PMID 36804487.
- PMID 36922627.
- PMID 32544925.
- PMID 32231295.
- PMID 15070904.
- PMID 12004055.
- PMID 18212250.
- S2CID 22465963.
- PMID 31141817.
External links
- "Opioid Receptors: κ". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2014-02-23. Retrieved 2007-07-23.
- kappa+Opioid+Receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)