Opioid receptor, kappa 1
Crystallographic structure of the human ?-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 2A0D, 2IQN, 4DJH
Identifiers
Symbols	OPRK1 ; K-OR-1; KOR; KOR-1; OPRK
External IDs	OMIM: 165196 MGI: 97439 HomoloGene: 20253 IUPHAR: 318 ChEMBL: 237 GeneCards: OPRK1 Gene
Gene ontology Molecular function • opioid receptor activity • protein binding • dynorphin receptor activity • neuropeptide binding Cellular component • plasma membrane • integral component of plasma membrane • integral component of membrane • dendrite • neuron projection • perikaryon • axon terminus • synapse Biological process • immune response • adenylate cyclase-inhibiting G-protein coupled receptor signaling pathway • phospholipase C-activating G-protein coupled receptor signaling pathway • neuropeptide signaling pathway • synaptic transmission • sensory perception • behavior • locomotory behavior • response to radiation • sensory perception of pain • adenylate cyclase-inhibiting opioid receptor signaling pathway • response to insulin • positive regulation of dopamine secretion • negative regulation of luteinizing hormone secretion • opioid receptor signaling pathway • positive regulation of locomotion • maternal behavior • eating behavior • response to morphine • response to estrogen • estrous cycle • response to ethanol • regulation of saliva secretion • behavioral response to cocaine • sensory perception of temperature stimulus • defense response to virus • regulation of sensory perception of pain • cellular response to lipopolysaccharide • positive regulation of p38MAPK cascade • positive regulation of potassium ion transmembrane transport • regulation of aerobic respiration • response to acrylamide • regulation of energy homeostasis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4986	18387
Ensembl	ENSG00000082556	ENSMUSG00000025905
UniProt	P41145	P33534
RefSeq (mRNA)	NM_000912	NM_001204371
RefSeq (protein)	NP_000903	NP_001191300
Location (UCSC)	Chr 8: 53.23 – 53.25 Mb	Chr 1: 5.59 – 5.61 Mb
PubMed search	[1]	[2]

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).^[2] 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.

Distribution[edit]

KORs 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 KOR 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 KOR protein with other membrane associated proteins.^[8]

Function[edit]

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. ^[9] More recent studies have shown the aversive properties in a variety of ways.^[10]

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.^[11]

The involvement of the KOR in stress, as well as in consequences of chronic stress such as depression, anxiety, anhedonia, and increased drug-seeking behavior, has been elucidated.^[9]

Activation of the KOR appears to antagonize many of the effects of the MOR.^[12]

KOR agonists are also known for their characteristic diuretic effects, due to their negative regulation of antidiuretic hormone (ADH).^[13]

KOR agonism is neuroprotective against hypoxia/ischemia; as such, KORs may represent a novel therapeutic target.^[14]

The selective KOR agonist U-50488 protected rats against supramaximal electroshock seizures, indicating that KOR agonism may have anticonvulsant effects.^[15]

Signal transduction[edit]

KOR activation by agonists is coupled to the G protein G_i/G₀, which subsequently increases phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurons.^[16][17][18] KORs also couple to inward-rectifier potassium^[19] and to N-type calcium ion channels.^[20] 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.^{[21][22][23][24][25][26]}

Ligands[edit]

The synthetic alkaloid ketazocine^[27] and terpenoid natural product salvinorin A^[11] are potent and selective KOR agonists. The KOR also mediates the dysphoria and hallucinations seen with opioids such as pentazocine.^[28]

22-Thiocyanatosalvinorin A (RB-64) is a functionally-selective κ-opioid receptor agonist.

Agonists[edit]

Antagonists[edit]

Natural agonists[edit]

Mentha spp.[edit]

Found in numerous species of mint, (including peppermint, spearmint, and watermint), the naturally-occurring compound menthol is a weak KOR agonist^[38] 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).^[39]

Salvia divinorum[edit]

The key compound in Salvia divinorum, salvinorin A, is known as a powerful, short-acting KOR agonist.^[40][41]

Ibogaine[edit]

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^[42] and this property may contribute to the drug's anti-addictive efficacy.

Role in treatment of drug addiction[edit]

KOR agonists have recently been investigated for their therapeutic potential in the treatment of addiction^[43] and evidence points towards dynorphin, the endogenous KOR agonist, to be the body's natural addiction control mechanism.^[44] Childhood stress/abuse is a well known predictor of drug abuse and is reflected in alterations of the MOR and KOR systems.^[45] 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.^[46][47]

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.^[48] In addition to low NAcc D2 binding,^[49][50] 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.^[51]

Additionally, while cocaine overdose victims showed a large increase in KORs (doubled) in the NAcc,^[52] KOR agonist administration is shown to be effective in decreasing cocaine seeking and self-administration.^[53] Furthermore, while cocaine abuse is associated with lowered prolactin response,^[54] KOR activation causes a release in prolactin,^[55] a hormone known for its important role in learning, neuronal plasticity and myelination.^[56]

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.^[57][58] 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.^[59] 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.^[24][60]

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.^[10] 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.^[61] There are numerous studies that reflect a reduction in self-administration of alcohol,^[62] and heroin dependence has also been shown to be effectively treated with KOR agonism by reducing the immediate rewarding effects^[63] and by causing the curative effect of up-regulation (increased production) of MORs^[64] 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^[65] 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[edit]

Selective KOR antagonists, including ALKS-5461 (a combination formulation of buprenorphine and samidorphan), and CERC-501 (LY-2456302), are in clinical trials for the treatment of depression and drug addiction.^[66] 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).^[66]

Interactions[edit]

KOR has been shown to interact with sodium-hydrogen antiporter 3 regulator 1^[67][68] and ubiquitin C.^[69]

See also[edit]

• δ-opioid receptor
• μ-opioid receptor

References[edit]

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)