| Opioid receptor, kappa 1 |
Crystallographic structure of the human κ-opioid receptor homo dimer (4djh) imbedded in a cartoon representation of a lipid bilayer. Each monomer is individually rainbow color-ed (N-terminus = blue, C-terminus = red). The receptor is bound to the ligand JDTic.[1] |
| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
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4DJH
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| Identifiers |
| Symbols |
OPRK1; KOR; OPRK |
| External IDs |
OMIM: 165196 MGI: 97439 HomoloGene: 20253 IUPHAR: κ ChEMBL: 237 GeneCards: OPRK1 Gene |
| Gene Ontology |
| Molecular function |
• protein binding
• dynorphin receptor activity
|
| Cellular component |
• plasma membrane
• integral to plasma membrane
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| Biological process |
• immune response
• adenylate cyclase-inhibiting G-protein coupled receptor signaling pathway
• phospholipase C-activating G-protein coupled receptor signaling pathway
• synaptic transmission
• sensory perception
• behavior
• opioid receptor signaling pathway
• defense response to virus
|
| Sources: Amigo / QuickGO |
|
| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
|
| Entrez |
4986 |
18387 |
|
| Ensembl |
ENSG00000082556 |
ENSMUSG00000025905 |
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| UniProt |
P41145 |
P33534 |
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| RefSeq (mRNA) |
NM_000912 |
NM_001204371 |
|
| RefSeq (protein) |
NP_000903 |
NP_001191300 |
|
| Location (UCSC) |
Chr 8:
54.14 – 54.16 Mb |
Chr 1:
5.59 – 5.61 Mb |
|
| PubMed search |
[1] |
[2] |
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The κ-opioid receptor (KOR) is a protein that in humans is encoded by the OPRK1 gene. The κ-opioid receptor is one of five related receptors that bind opium-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering the perception of pain, consciousness, motor control, and mood.
The κ-opioid receptor is a type of opioid receptor that binds the opioid peptide dynorphin as the primary endogenous ligand (substrate naturally occurring in the body).[2] In addition to dynorphin, a variety of natural alkaloids and synthetic ligands bind to the receptor. The κ-opioid receptor may provide a natural addiction control mechanism, and therefore, drugs that act as agonists and increase activation of this receptor may have therapeutic potential in the treatment of addiction.
Contents
- 1 Distribution
- 2 Subtypes
- 3 Function
- 4 Signal transduction
- 5 Ligands
- 5.1 Agonists
- 5.2 Antagonists
- 5.3 Natural agonists
- 5.3.1 Mentha spp.
- 5.3.2 Salvia divinorum
- 5.3.3 Ibogaine
- 6 Role in treatment of drug addiction
- 7 Interactions
- 8 See also
- 9 References
- 10 External links
Distribution[edit]
κ-Opioid receptors are widely distributed in the brain (hypothalamus, periaqueductal gray, and claustrum), spinal cord (substantia gelatinosa), and in pain neurons.[3][4]
Subtypes[edit]
Based on receptor binding studies, three variants of the κ-opioid receptor designated κ1, κ2, and κ3 have been characterized.[5][6] However only one cDNA clone has been identified,[7] hence these receptor subtypes likely arise from interaction of one κ-opioid receptor protein with other membrane associated proteins.[8]
Function[edit]
It has long been understood that κ-opioid receptor agonists are dysphoric[9] but dysphoria from κ-opioid receptor agonists has been shown to differ between the sexes.[10][11] More recent studies have shown the aversive properties in a variety of ways[12] and the κ-opioid receptor has been strongly implicated as an integral neurochemical component of addiction and the remission thereof.
It is now widely accepted that κ-opioid receptor (partial) agonists have dissociative and delirium-inducing effects, as exemplified by salvinorin A. These effects are generally undesirable in medicinal drugs and could have had frightening or disturbing effects in the tested humans. It is thought that the hallucinogenic effects of drugs such as butorphanol, nalbuphine, and pentazocine serve to limit their opiate abuse potential. In the case of salvinorin A, a structurally novel neoclerodane diterpene κ-opioid receptor agonist, these hallucinogenic, more specifically deliriant and dissociative, effects are sought after, even though the experience is often considered dysphoric by the user. While salvinorin A is considered a hallucinogen, its effects are qualitatively different than those produced by the classical psychedelic hallucinogens such as LSD or mescaline.[13]
The involvement of the κ-opioid receptor in stress response has been elucidated.[9]
Activation of the κ-opioid receptor appears to antagonize many of the effects of the μ-opioid receptor.[14]
κ-Opioid receptor ligands are also known for their characteristic diuretic effects, due to their negative regulation of antidiuretic hormone (ADH).[15]
κ-Opioid agonism is neuroprotective against hypoxia/ischemia; as such, κ-opioid receptors may represent a novel therapeutic target.[16]
The selective κ-opioid agonist U-50488 protected rats against supramaximal electroshock seizures, indicating that κ-opioid agonism may have anticonvulsant effects.[17]
Signal transduction[edit]
κ-Opioid receptor activation by agonists is coupled to the G protein Gi/G0, which subsequently increases phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurons.[18][19][20] κ-Opioid receptors also couple to inward-rectifier potassium[21] and to N-type calcium ion channels.[22] Recent studies have also demonstrated that agonist-induced stimulation of the κ-Opioid receptor, like other G-protein coupled receptors, can result in the activation of mitogen-activated protein kinases (MAPK). These include extracellular signal-regulated kinase, p38 MAP kinases, and c-Jun N-terminal kinases.[23][24][25][26][27][28]
Ligands[edit]
|
This section's factual accuracy is disputed. (March 2013) |
The synthetic alkaloid ketazocine[29] and terpenoid natural product salvinorin A[13] are potent and selective κ-opioid receptor agonists. The κ-opioid receptor also mediates the action of the hallucinogenic side effects of opioids such as pentazocine.[30]
Agonists[edit]
- Asimadoline
- Bremazocine
- Butorphanol
- BRL-52537
- Cyclazocine
- Dynorphin (endogenous peptide ligand)
- Enadoline
- FE 200665
- GR-89696 - selective for κ2 subtype
- HZ-2
- ICI-204,448 - peripherally selective
- ICI-199,441
- Ketazocine
- Levallorphan
- LPK-26 - highly selective
- Menthol
- Nalbuphine
- Nalfurafine
- Norbuprenorphine
- Oxycodone (disputed)
- Pentazocine
- Salvinorin A
- 2-Methoxymethyl Salvinorin B[31] and its ethoxymethyl and fluoroethoxymethyl homologues[32][33]
- Spiradoline
- Tifluadom
- U-50488
- U-69593
Antagonists[edit]
- 5'-Guanidinonaltrindole
- Buprenorphine[34]
- Norbinaltorphimine
- JDTic
- Amentoflavone[35]
Natural agonists[edit]
Mentha spp.[edit]
Main article: menthol
Found in numerous species of mint, (including peppermint, spearmint, and watermint), the naturally-occurring compound Menthol is a weak k-opioid receptor agonist[36] 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).[37]
Salvia divinorum[edit]
Main article: Salvia divinorum
The key compound in Salvia divinorum, Salvinorin A, is known as a non-toxic yet potent κ-opioid agonist.[38][39]
Ibogaine[edit]
Main article: 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 κ-opioid agonist[40] and this property may contribute to the drug's anti-addictive efficacy.
Role in treatment of drug addiction[edit]
κ-Opioid agonists have recently been investigated for their therapeutic potential in the treatment of addiction[41] and evidence points towards dynorphin, the endogenous κ-opioid agonist, to be the body's natural addiction control mechanism.[42] Childhood stress/abuse is a well known predictor of drug abuse and is reflected in alterations of the μ- and κ-opioid systems.[43] In experimental "addiction" models the κ-opioid receptor 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 κ-opioid receptors are required for stress-induced reinstatement of cocaine seeking.[44][45]
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.[46] In addition to low NAcc D2 binding,[47][48] 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 κ-opioid agonist produced an opposite effect causing an increase in D2 receptors in the NAcc.[49]
Additionally, while cocaine overdose victims showed a large increase in κ-opioid receptors (doubled) in the NAcc,[50] κ-opioid agonist administration is shown to be effective in decreasing cocaine seeking and self-administration.[51] Furthermore, while cocaine abuse is associated with lowered prolactin response,[52] κ-opioid activation causes a release in prolactin,[53] a hormone known for its important role in learning, neuronal plasticity and myelination.[54]
It has also been reported that the κ-opioid 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.[55][56] These effects are likely caused by stress-induced drug craving that requires activation of the κ-opioid 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[57] The rewarding properties of drug are altered, and it is clear κ-opioid 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 κ-opioid receptors is likely due to multiple signaling mechanisms. The effects of κ-opioid agonism on dopamine systems are well documented, and recent work also implicates the mitogen-activated protein kinase cascade and pCREB in κ-opioid dependent behaviors. [26][58]
Though cocaine abuse is a frequently used model of addiction, κ-opioid agonists have very marked effects on all types of addiction including alcohol, cocaine and opiate abuse.[12] Not only are genetic differences in dynorphin receptor expression a marker for alcohol dependence but a single dose of a κ-opioid antagonist markedly increased alcohol consumption in lab animals.[59] There are numerous studies that reflect a reduction in self-administration of alcohol,[60] and heroin dependence has also been shown to be effectively treated with κ-opioid agonism by reducing the immediate rewarding effects[61] and by causing the curative effect of up-regulation (increased production) of μ-opioid receptors[62] that have been down-regulated during opioid abuse.
The anti-rewarding properties of κ-opioid agonists are mediated through both long-term and short-term effects. The immediate effect of κ-opioid agonism leads to reduction of dopamine release in the NAcc during self administration of cocaine[63] and over the long term up-regulates receptors that have been down-regulated during substance abuse such as μ-opioid and D2 receptors. These receptors modulate the release of other neurochemicals such as serotonin in the case of μ-opioid receptor 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 κ-opioid agonism (30 minutes or greater) have been linked to κ-opioid receptor-dependent stress-induced potentiation and reinstatement of drug seeking. It is hypothesized that these behaviors are mediated by κ-opioid-dependent modulation of dopamine, serotonin, or norepinephrine and/or via activation of downstream signal transduction pathways.
Interactions[edit]
The κ-opioid receptor has been shown to interact with sodium-hydrogen antiporter 3 regulator 1[64][65] and ubiquitin C.[66]
See also[edit]
- Opioid receptor
- Δ-opioid receptor
References[edit]
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- ^ Patkar AA, Mannelli P, Hill KP, Peindl K, Pae CU, Lee TH (August 2006). "Relationship of prolactin response to meta-chlorophenylpiperazine with severity of drug use in cocaine dependence". Human psychopharmacology 21 (6): 367–75. doi:10.1002/hup.780. PMID 16915581.
- ^ Butelman ER, Kreek MJ (July 2001). "kappa-Opioid receptor agonist-induced prolactin release in primates is blocked by dopamine D(2)-like receptor agonists". European Journal of Pharmacology 423 (2–3): 243–9. doi:10.1016/S0014-2999(01)01121-9. PMID 11448491.
- ^ Gregg C, Shikar V, Larsen P, Mak G, Chojnacki A, Yong VW, Weiss S (February 2007). "White matter plasticity and enhanced remyelination in the maternal CNS". Journal of Neuroscience 27 (8): 1812–23. doi:10.1523/JNEUROSCI.4441-06.2007. PMID 17314279.
- ^ McLaughlin JP, Marton-Popovici M, Chavkin C. (July 2003). "Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses". Journal of Neuroscience 23 (13): 5674–83. PMC 2104777. PMID 12843270.
- ^ Mash, DEBORAH C.; Li, S; Valdez, J; Chavkin, TA; Chavkin, C (June 2006). "Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system". Neuropsychopharmacology 31 (4): 787–94. doi:10.1038/sj.npp.1300872. PMC 2096774. PMID 16123746.
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- ^ Narita M, Khotib J, Suzuki M, Ozaki S, Yajima Y, Suzuki T (June 2003). "Heterologous mu-opioid receptor adaptation by repeated stimulation of kappa-opioid receptor: up-regulation of G-protein activation and antinociception". Journal of Neurochemistry 85 (5): 1171–9. doi:10.1046/j.1471-4159.2003.01754.x. PMID 12753076.
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External links[edit]
- "Opioid Receptors: κ". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- kappa Opioid Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
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Cell surface receptor: G protein-coupled receptors
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Class A:
Rhodopsin like |
|
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| Class B: Secretin like |
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Orphan
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- GPR (56
- 64
- 97
- 98
- 110
- 111
- 112
- 113
- 114
- 115
- 116
- 123
- 124
- 125
- 126
- 128
- 133
- 143
- 144
- 155
- 157)
|
|
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Other
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- Brain-specific angiogenesis inhibitor (1
- 2
- 3)
- Cadherin (1
- 2
- 3)
- Calcitonin
- CALCRL
- CD97
- Corticotropin-releasing hormone (1
- 2)
- EMR (1
- 2
- 3)
- Glucagon (GR
- GIPR
- GLP1R
- GLP2R)
- Growth hormone releasing hormone
- PACAPR1
- GPR
- Latrophilin (1
- 2
- 3
- ELTD1)
- Methuselah-like proteins
- Parathyroid hormone (1
- 2)
- Secretin
- Vasoactive intestinal peptide (1
- 2)
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|
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Class C: Metabotropic
glutamate / pheromone |
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Taste
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- TAS1R (1
- 2
- 3)
- TAS2R (1
- 3
- 4
- 5
- 7
- 8
- 9
- 10
- 13
- 14
- 16
- 19
- 20
- 30
- 31
- 38
- 39
- 40
- 41
- 42
- 43
- 45
- 46
- 50
- 60)
|
|
|
Other
|
- Calcium-sensing receptor
- GABA B (1
- 2)
- Glutamate receptor (Metabotropic glutamate (1
- 2
- 3
- 4
- 5
- 6
- 7
- 8))
- GPRC6A
- GPR (156
- 158
- 179)
- RAIG (1
- 2
- 3
- 4)
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|
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Class F:
Frizzled / Smoothened |
|
Frizzled
|
- Frizzled (1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 9
- 10)
|
|
|
Smoothened
|
|
|
|
|
B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
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Neuropeptide receptors
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| G protein-coupled receptor |
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Hormone receptors
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Hypothalamic
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CRH · FSH · LHRH · TRH · Somatostatin
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Pituitary
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Vasopressin (1A, 1B, 2) · Oxytocin · LHCG · TSH
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Other
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Atrial natriuretic factor (NPR3) · Calcitonin · Cholecystokinin (A, B) · VIP
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Opioid receptors
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Delta · Kappa · Mu · Nociceptin
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Other neuropeptide receptors
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Angiotensin · Bradykinin (B1, B2) / Tachykinin (TACR1) · Calcitonin gene-related peptide · Galanin · GPCR neuropeptide (B/W, FF, S, Y) · Neurotensin
|
|
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| Type I cytokine receptor |
GH · Prolactin
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| Enzyme-linked receptor |
Atrial natriuretic factor (NPR1, NPR2)
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| Other |
Sigma (1, 2)
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|
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B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
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|