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κ-opioid receptor

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Template:PBB The κ-Opioid receptor is a type of opioid receptor which binds the peptide opioid dynorphin as the primary endogenous ligand.[1] κ receptors are widely distributed in the brain (hypothalamus, periaqueductal gray, and claustrum), spinal cord (substantia gelatinosa), and in pain neurons.[2][3]

Receptor subtypes

Based on receptor binding studies, three variants of the κ-opioid receptor designated κ1, κ2, and κ3 have been characterized.[4][5] However only one cDNA clone has been identified,[6] hence these receptor subtypes likely arise from interaction of one κ-opioid receptor protein with other membrane associated proteins.[7]

Function

It has long been understood that kappa-opioid receptor agonists are dysphoric[8] but dysphoria from kappa opioids has been shown to differ between sexes[9][10] More recent studies have shown the aversive properties in a variety of ways[11] and the kappa 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 hallucinogenic 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 effects are sought after. 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.[12]

The involvement of the kappa-opioid receptor in stress response has been elucidated.[8]

Activation of the κ-opioid receptor appears to antagonize many of the effects of the μ opioid receptor.[13]

Kappa ligands are also known for their characteristic diuretic effects, due to their negative regulation of antidiuretic hormone (ADH).[14]

Kappa agonism is neuroprotective against hypoxia/ischemia; as such, kappa receptors may represent a novel therapeutic target.[15]

Signal transduction

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.[16][17][18] κ-Opioid receptors 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 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.[21][22][23][24][25][26]

Ligands

The synthetic alkaloid ketazocine[27] and terpenoid natural product salvinorin A[12] 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.[28]

Agonists

Antagonists

Natural agonists

Mentha spp.

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[32] owing to its antinociceptive effects in rats. In addition, mints can desensitize a region through the activation of TRPM8 receptors (the 'cold'/menthol receptor).[33]

Salvia divinorum

Main article: salvia divinorum

The key compound in Salvia divinorum, Salvinorin A, is known as a non-toxic yet potent kappa-opioid agonist.[34][35]

Ibogaine

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, hence it is considered illegal to possess under any circumstances. Ibogaine is also a kappa opioid agonist[36] and this property may contribute to the drug's anti-addictive efficacy.

Role in Treatment of Drug Addiction

Kappa opioids have recently been investigated for their therapeutic potential in the treatment of addiction[37] and evidence points towards dynorphin, the endogenous kappa agonist, to be the body's natural addiction control mechanism.[38] Childhood stress/abuse is a well known predictor of drug abuse and is reflected in alterations of the mu and kappa opioid systems.[39] In experimental "addiction" models the Kappa-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 Kappa-opioid receptors are required for stress-induced reinstatement of cocaine seeking.[40][41]

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.[42] In addition to low NAcc D2 binding,[43][44] 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 kappa agonist produced an opposite effect causing an increase in D2 receptors in the NAcc.[45]

Additionally, while cocaine overdose victims showed a large increase in kappa receptors (doubled) in the NAcc,[46] kappa opioid agonist administration is shown to be effective in decreasing cocaine seeking and self-administration.[47] Furthermore, while cocaine abuse is associated with lowered prolactin response,[48] kappa opioid activation causes a release in prolactin,[49] a hormone known for its important role in learning, neuronal plasticity and myelination.[50]

It has also been reported that the dynorphin-Kappa 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.[51][52] These effects are likely caused by stress-induced drug craving that requires activation of the dynorphin/kappa 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[53] The rewarding properties of drug are altered, and it is clear kappa-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 Kappa opioid receptors is likely due to multiple signaling mechanisms. The effects of kappa-opioid agonism on dopamine systems are well documented, and recent work also implicates the mitogen-activated protein kinase cascade and pCREB in Kappa-opioid dependent behaviors. [24][54]

Though cocaine abuse is a frequently used model of addiction, kappa opioids have very marked effects on all types of addiction including alcohol and opiate abuse.[11] Not only are genetic differences in dynorphin receptor expression a marker for alcohol dependence, but a single dose of a kappa opioid antagonist markedly increased alcohol consumption in lab animals.[55] There are numerous studies which reflect a reduction in self-administration of alcohol,[56] and heroin dependence has also been shown to be effectively treated with kappa agonism by reducing the immediate rewarding effects[57] and by causing the curative effect of up-regulation of mu-opioid receptors[58] which have been down-regulated during opioid abuse.

The anti-rewarding properties of kappa opioid agonists are mediated through both long-term and short-term effects. The immediate effect of kappa agonism leads to reduction of dopamine release in the NAcc during self administration of cocaine[59] and over the long term up-regulates receptors which have been down-regulated during substance abuse such as mu-opioid and D2 (dopamine) receptors. These receptors modulate the release of other neurochemicals such as serotonin in the case of mu-opioids 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 kappa opioid agonism (30 minutes or greater) have been linked to kappa opioid dependent stress-induced potentiation and reinstatement of drug seeking. It is hypothesized that these behaviors are mediated by kappa opioid-dependent modulation of dopamine, serotonin, or norepinephrine and/or via activation of downstream signal transduction pathways.

Interactions

Kappa Opioid receptor has been shown to interact with Sodium-hydrogen antiporter 3 regulator 1[60][61] and Ubiquitin C.[62]

References

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