Κ-opioid receptor

The κ-opioid receptor (KOR) is a is_associated_with::protein that in humans is encoded by the OPRK1 is_associated_with::gene. The KOR is one of four related receptors that bind is_associated_with::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 is_associated_with::opioid receptor that binds the is_associated_with::opioid is_associated_with::peptide is_associated_with::dynorphin as the primary endogenous ligand (substrate naturally occurring in the body). In addition to dynorphin, a variety of natural is_associated_with::alkaloids and synthetic ligands bind to the receptor. The KOR may provide a natural addiction control mechanism, and therefore, drugs that act as is_associated_with::agonists and increase activation of this receptor may have therapeutic potential in the treatment of addiction.

Distribution
KORs are widely distributed in the is_associated_with::brain (is_associated_with::hypothalamus, is_associated_with::periaqueductal gray, and is_associated_with::claustrum), is_associated_with::spinal cord (substantia gelatinosa), and in pain is_associated_with::neurons.

Subtypes
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.

Function
Similarly to μ-opioid receptor (MOR) agonists, KOR agonists are is_associated_with::analgesic. However, KOR agonists also produce side effects such as is_associated_with::dysphoria and is_associated_with::hallucinations, which limits their clinical usefulness. More recent studies have shown the aversive properties in a variety of ways.

Some KOR agonists have is_associated_with::dissociative and hallucinogenic effects, as exemplified by is_associated_with::salvinorin A. These effects are generally undesirable in medicinal drugs. It is thought that the is_associated_with::hallucinogenic effects of drugs such as is_associated_with::butorphanol, is_associated_with::nalbuphine, and is_associated_with::pentazocine serve to limit their opioid abuse potential. In the case of salvinorin A, a structurally novel is_associated_with::neoclerodane is_associated_with::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 is_associated_with::LSD, is_associated_with::mescaline or is_associated_with::psilocybin.

The involvement of the KOR in stress, as well as in consequences of is_associated_with::chronic stress such as depression, is_associated_with::anxiety, is_associated_with::anhedonia, and increased drug-seeking behavior, has been elucidated.

Activation of the KOR appears to antagonize many of the effects of the MOR.

KOR agonists are also known for their characteristic is_associated_with::diuretic effects, due to their negative regulation of is_associated_with::antidiuretic hormone (ADH).

KOR agonism is neuroprotective against hypoxia/is_associated_with::ischemia; as such, KORs may represent a novel therapeutic target.

The selective KOR agonist is_associated_with::U-50488 protected rats against supramaximal is_associated_with::electroshock is_associated_with::seizures, indicating that KOR agonism may have is_associated_with::anticonvulsant effects.

Signal transduction
KOR activation by agonists is coupled to the is_associated_with::G protein Gi/G0, which subsequently increases is_associated_with::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 is_associated_with::G-protein coupled receptors, can result in the activation of is_associated_with::mitogen-activated protein kinases (MAPK). These include is_associated_with::extracellular signal-regulated kinase, is_associated_with::p38 MAP kinases, and is_associated_with::c-Jun N-terminal kinases.

Ligands
The synthetic alkaloid is_associated_with::ketazocine and terpenoid natural product is_associated_with::salvinorin A are potent and selective KOR is_associated_with::agonists. The KOR also mediates the is_associated_with::dysphoria and is_associated_with::hallucinations seen with opioids such as is_associated_with::pentazocine.



Agonists

 * is_associated_with::8-Carboxamidocyclazocine
 * is_associated_with::Alazocine– partial agonist
 * is_associated_with::Asimadoline – peripherally-selective
 * is_associated_with::Bremazocine – highly selective
 * is_associated_with::Butorphanol – partial agonist
 * is_associated_with::BRL-52537
 * is_associated_with::CR845 – peripherally-selective
 * is_associated_with::Cyclazocine – partial agonist
 * is_associated_with::Dextromethorphan
 * is_associated_with::Dynorphins (is_associated_with::dynorphin A, is_associated_with::dynorphin B, is_associated_with::big dynorphin) – endogenous peptides
 * is_associated_with::Enadoline
 * is_associated_with::Erinacine E
 * is_associated_with::Etorphine
 * FE 200665 (CR665) – peripherally-selective
 * is_associated_with::GR-89696 – selective for κ2
 * is_associated_with::HS665
 * is_associated_with::HZ-2
 * is_associated_with::Ibogaine – naturally-occurring
 * is_associated_with::ICI-204,448 – peripherally-selective
 * is_associated_with::ICI-199,441
 * is_associated_with::Ketamine
 * is_associated_with::Ketazocine
 * is_associated_with::Levallorphan
 * is_associated_with::Levorphanol
 * is_associated_with::LPK-26 – highly selective
 * is_associated_with::MB-1C-OH
 * is_associated_with::Menthol – naturally-occurring
 * is_associated_with::Metazocine – partial agonist
 * is_associated_with::Morphine – naturally-occurring
 * is_associated_with::N-MPPP
 * is_associated_with::Nalbuphine – partial agonist
 * is_associated_with::Nalfurafine
 * is_associated_with::Nalmefene – partial agonist
 * is_associated_with::Nalorphine – partial agonist
 * is_associated_with::Norbuprenorphine – partial agonist; peripherally-selective metabolite of buprenorphine
 * is_associated_with::Norbuprenorphine-3-glucuronide – likely partial agonist; peripherally-selective metabolite of buprenorphine
 * is_associated_with::Oxycodone – selective for κ2b subtype
 * is_associated_with::Pentazocine – partial agonist
 * is_associated_with::Phenazocine
 * is_associated_with::Eluxadoline
 * is_associated_with::RB-64 (22-thiocyanatosalvinorin A) – G protein is_associated_with::biased agonist with a bias factor of 96
 * is_associated_with::Salvinorin A – naturally-occurring
 * 2-Methoxymethyl salvinorin B – and its ethoxymethyl and fluoroethoxymethyl homologues
 * is_associated_with::Spiradoline
 * is_associated_with::Tifluadom
 * is_associated_with::U-50,488
 * is_associated_with::U-54,494A
 * is_associated_with::U-69,593
 * is_associated_with::Xorphanol – partial agonist

Antagonists

 * is_associated_with::5'-Acetamidinoethylnaltrindole (ANTI) – selective
 * is_associated_with::5'-Guanidinonaltrindole (5'-GNTI) – selective, long-acting
 * is_associated_with::Amentoflavone – non-selective; naturally-occurring
 * is_associated_with::AT-076 – non-selective, likely long acting; JDTic analogue
 * is_associated_with::Binaltorphimine – selective, long-acting
 * is_associated_with::BU09059 – selective, short-acting; JDTic analogue
 * is_associated_with::Buprenorphine – non-selective; silent antagonist or weak partial agonist, depending on source
 * is_associated_with::CERC-501 – selective, short-acting
 * is_associated_with::Dezocine – non-selective; silent antagonist
 * is_associated_with::DIPPA – selective, long-acting
 * is_associated_with::Diprenorphine – non-selective; maybe weak partial agonist
 * is_associated_with::JDTic – selective, long-acting
 * is_associated_with::LY-255582 - non-selective
 * is_associated_with::LY-2459989 – selective, short-acting
 * is_associated_with::LY-2795050 – selective, short-acting
 * is_associated_with::Methylnaltrexone – non-selective
 * is_associated_with::ML190 – selective
 * is_associated_with::ML350 – selective, short-acting
 * is_associated_with::MR-2266 – non-selective
 * is_associated_with::Naloxone – non-selective
 * is_associated_with::Naltrexone – non-selective
 * is_associated_with::Noribogaine – non-selective; naturally-occurring
 * is_associated_with::Norbinaltorphimine – selective, long-acting
 * is_associated_with::Pawhuskin A – selective; naturally-occurring
 * is_associated_with::PF-4455242 – selective, short-acting
 * is_associated_with::Quadazocine – non-selective; silent antagonist; preference for κ2
 * is_associated_with::Zyklophin – selective peptide antagonist; dynorphin A analogue

Mentha spp.
Found in numerous species of mint, (including is_associated_with::peppermint, is_associated_with::spearmint, and is_associated_with::watermint), the naturally-occurring compound is_associated_with::menthol is a weak KOR agonist owing to its is_associated_with::antinociceptive, or pain blocking, effects in rats. In addition, mints can desensitize a region through the activation of is_associated_with::TRPM8 receptors (the 'cold'/menthol receptor).

Salvia divinorum
The key compound in is_associated_with::Salvia divinorum, is_associated_with::salvinorin A, is known as a powerful, short-acting KOR agonist.

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 is_associated_with::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 is_associated_with::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 is_associated_with::nucleus accumbens (NAcc) and is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::homeostasis to is_associated_with::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 is_associated_with::neurochemicals such as is_associated_with::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 is_associated_with::dopamine, is_associated_with::serotonin, or is_associated_with::norepinephrine and/or via activation of downstream signal transduction pathways.

Future clinical prospects
Selective KOR antagonists, including is_associated_with::ALKS-5461 (a combination formulation of is_associated_with::buprenorphine and is_associated_with::samidorphan), and is_associated_with::CERC-501 (LY-2456302), are in is_associated_with::clinical trials for the treatment of depression and is_associated_with::drug addiction. is_associated_with::JDTic and is_associated_with::PF-4455242 were also under investigation but development was halted in both cases due to toxicity concerns (unrelated to their KOR antagonist properties).

Interactions
The KOR has been shown to interact with is_associated_with::sodium-hydrogen antiporter 3 regulator 1 and is_associated_with::ubiquitin C.