|Opioid receptor, kappa 1|
Crystallographic structure of the human ?-opioid receptor homo dimer ( ) 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.
|Symbols||; K-OR-1; KOR; KOR-1; OPRK|
|External IDs||IUPHAR: ChEMBL: GeneCards:|
|RNA expression pattern|
The κ-opioid receptor (KOR) is a protein that in humans is encoded by the OPRK1 gene. The KOR is one of four related receptors that bind opiate-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering the perception of pain, consciousness, motor control, and mood.
The KOR is a type of opioid receptor that binds the opioid peptide dynorphin as the primary endogenous ligand (substrate naturally occurring in the body). In addition to dynorphin, a variety of natural alkaloids and synthetic ligands bind to the receptor. The KOR may provide a natural addiction control mechanism, and therefore, drugs that act as agonists and increase activation of this receptor may have therapeutic potential in the treatment of addiction.
Based on receptor binding studies, three variants of the KOR designated κ1, κ2, and κ3 have been characterized. However only one cDNA clone has been identified, hence these receptor subtypes likely arise from interaction of one KOR protein with other membrane associated proteins.
Similarly to μ-opioid receptor (MOR) agonists, KOR agonists are analgesic. However, KOR agonists also produce side effects such as dysphoria and hallucinations, which limits their clinical usefulness.  More recent studies have shown the aversive properties in a variety of ways.
Some KOR agonists have dissociative and hallucinogenic effects, as exemplified by salvinorin A. These effects are generally undesirable in medicinal drugs. It is thought that the hallucinogenic effects of drugs such as butorphanol, nalbuphine, and pentazocine serve to limit their opioid abuse potential. In the case of salvinorin A, a structurally novel neoclerodane diterpene KOR agonist, these hallucinogenic effects are sought after, even though the experience is often considered dysphoric by the user. While salvinorin A is considered a hallucinogen, its effects are qualitatively different than those produced by the classical psychedelic hallucinogens such as LSD, mescaline or psilocybin.
Activation of the KOR appears to antagonize many of the effects of the MOR.
KOR activation by agonists is coupled to the G protein Gi/G0, which subsequently increases phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurons. KORs also couple to inward-rectifier potassium and to N-type calcium ion channels. Recent studies have also demonstrated that agonist-induced stimulation of the KOR, like other G-protein coupled receptors, can result in the activation of mitogen-activated protein kinases (MAPK). These include extracellular signal-regulated kinase, p38 MAP kinases, and c-Jun N-terminal kinases.
The synthetic alkaloid ketazocine and terpenoid natural product salvinorin A are potent and selective KOR agonists. The KOR also mediates the dysphoria and hallucinations seen with opioids such as pentazocine.
- Alazocine– partial agonist
- Asimadoline – peripherally-selective
- Bremazocine – highly selective
- Butorphanol – partial agonist
- CR845 – peripherally-selective
- Cyclazocine – partial agonist
- Dynorphins (dynorphin A, dynorphin B, big dynorphin) – endogenous peptides
- Erinacine E
- FE 200665 (CR665) – peripherally-selective
- GR-89696 – selective for κ2
- Ibogaine – naturally-occurring
- ICI-204,448 – peripherally-selective
- LPK-26 – highly selective
- Menthol – naturally-occurring
- Metazocine – partial agonist
- Morphine – naturally-occurring
- Nalbuphine – partial agonist
- Nalmefene – partial agonist
- Nalorphine – partial agonist
- Norbuprenorphine – partial agonist; peripherally-selective metabolite of buprenorphine
- Norbuprenorphine-3-glucuronide – likely partial agonist; peripherally-selective metabolite of buprenorphine
- Oxycodone – selective for κ2b subtype
- Pentazocine – partial agonist
- RB-64 (22-thiocyanatosalvinorin A) – G protein biased agonist with a bias factor of 96
- Salvinorin A – naturally-occurring
- 2-Methoxymethyl salvinorin B – and its ethoxymethyl and fluoroethoxymethyl homologues
- Xorphanol – partial agonist
- 5'-Acetamidinoethylnaltrindole (ANTI) – selective
- 5'-Guanidinonaltrindole (5'-GNTI) – selective, long-acting
- Amentoflavone – non-selective; naturally-occurring
- AT-076 – non-selective, likely long acting; JDTic analogue
- Binaltorphimine – selective, long-acting
- BU09059 – selective, short-acting; JDTic analogue
- Buprenorphine – non-selective; silent antagonist or weak partial agonist, depending on source
- CERC-501 – selective, short-acting
- Dezocine – non-selective; silent antagonist
- DIPPA – selective, long-acting
- Diprenorphine – non-selective; maybe weak partial agonist
- JDTic – selective, long-acting
- LY-255582 - non-selective
- LY-2459989 – selective, short-acting
- LY-2795050 – selective, short-acting
- Methylnaltrexone – non-selective
- ML190 – selective
- ML350 – selective, short-acting
- MR-2266 – non-selective
- Naloxone – non-selective
- Naltrexone – non-selective
- Noribogaine – non-selective; naturally-occurring
- Norbinaltorphimine – selective, long-acting
- Pawhuskin A – selective; naturally-occurring
- PF-4455242 – selective, short-acting
- Quadazocine – non-selective; silent antagonist; preference for κ2
- Zyklophin – selective peptide antagonist; dynorphin A analogue
Found in numerous species of mint, (including peppermint, spearmint, and watermint), the naturally-occurring compound menthol is a weak KOR agonist owing to its antinociceptive, or pain blocking, effects in rats. In addition, mints can desensitize a region through the activation of TRPM8 receptors (the 'cold'/menthol receptor).
Used for the treatment of addiction in limited countries, ibogaine has become an icon of addiction management among certain underground circles. Despite its lack of addictive properties, ibogaine is listed as a Schedule I compound in the US because it is a psychoactive substance, hence it is considered illegal to possess under any circumstances. Ibogaine is also a KOR agonist and this property may contribute to the drug's anti-addictive efficacy.
Role in treatment of drug addiction
KOR agonists have recently been investigated for their therapeutic potential in the treatment of addiction and evidence points towards dynorphin, the endogenous KOR agonist, to be the body's natural addiction control mechanism. Childhood stress/abuse is a well known predictor of drug abuse and is reflected in alterations of the MOR and KOR systems. In experimental "addiction" models the KOR has also been shown to influence stress-induced relapse to drug seeking behavior. For the drug-dependent individual, risk of relapse is a major obstacle to becoming drug-free. Recent reports demonstrated that KORs are required for stress-induced reinstatement of cocaine seeking.
One area of the brain most strongly associated with addiction is the nucleus accumbens (NAcc) and striatum while other structures that project to and from the NAcc also play a critical role. Though many other changes occur, addiction is often characterized by the reduction of dopamine D2 receptors in the NAcc. In addition to low NAcc D2 binding, cocaine is also known to produce a variety of changes to the primate brain such as increases prodynorphin mRNA in caudate putamen (striatum) and decreases of the same in the hypothalamus while the administration of a KOR agonist produced an opposite effect causing an increase in D2 receptors in the NAcc.
Additionally, while cocaine overdose victims showed a large increase in KORs (doubled) in the NAcc, KOR agonist administration is shown to be effective in decreasing cocaine seeking and self-administration. Furthermore, while cocaine abuse is associated with lowered prolactin response, KOR activation causes a release in prolactin, a hormone known for its important role in learning, neuronal plasticity and myelination.
It has also been reported that the KOR system is critical for stress-induced drug-seeking. In animal models, stress has been demonstrated to potentiate cocaine reward behavior in a kappa opioid-dependent manner. These effects are likely caused by stress-induced drug craving that requires activation of the KOR system. Although seemingly paradoxical, it is well known that drug taking results in a change from homeostasis to allostasis. It has been suggested that withdrawal-induced dysphoria or stress-induced dysphoria may act as a driving force by which the individual seeks alleviation via drug taking. The rewarding properties of drug are altered, and it is clear KOR activation following stress modulates the valence of drug to increase its rewarding properties and cause potentiation of reward behavior, or reinstatement to drug seeking. The stress-induced activation of KORs is likely due to multiple signaling mechanisms. The effects of KOR agonism on dopamine systems are well documented, and recent work also implicates the mitogen-activated protein kinase cascade and pCREB in KOR-dependent behaviors.
Though cocaine abuse is a frequently used model of addiction, KOR agonists have very marked effects on all types of addiction including alcohol, cocaine and opiate abuse. Not only are genetic differences in dynorphin receptor expression a marker for alcohol dependence but a single dose of a KOR antagonist markedly increased alcohol consumption in lab animals. There are numerous studies that reflect a reduction in self-administration of alcohol, and heroin dependence has also been shown to be effectively treated with KOR agonism by reducing the immediate rewarding effects and by causing the curative effect of up-regulation (increased production) of MORs that have been down-regulated during opioid abuse.
The anti-rewarding properties of KOR agonists are mediated through both long-term and short-term effects. The immediate effect of KOR agonism leads to reduction of dopamine release in the NAcc during self-administration of cocaine and over the long term up-regulates receptors that have been down-regulated during substance abuse such as the MOR and the D2 receptor. These receptors modulate the release of other neurochemicals such as serotonin in the case of MOR agonists and acetylcholine in the case of D2. These changes can account for the physical and psychological remission of the pathology of addiction. The longer effects of KOR agonism (30 minutes or greater) have been linked to KOR-dependent stress-induced potentiation and reinstatement of drug seeking. It is hypothesized that these behaviors are mediated by KOR-dependent modulation of dopamine, serotonin, or norepinephrine and/or via activation of downstream signal transduction pathways.
Future clinical prospects
Selective KOR antagonists, including ALKS-5461 (a combination formulation of buprenorphine and samidorphan), and CERC-501, are in clinical trials for the treatment of depression and drug addiction. JDTic and PF-4455242 were also under investigation but development was halted in both cases due to toxicity concerns (unrelated to their KOR antagonist properties).
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