κ-opioid receptor

The κ-opioid receptor (KOR) is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction. 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, terpenes and other synthetic ligands bind to the receptor. The KOR may provide a natural addiction control mechanism, and therefore, drugs that target this receptor may have therapeutic potential in the treatment of addiction. There is evidence that distribution and/or function of this receptor may differ between sexes. KORs are widely distributed in the brain, spinal cord (substantia gelatinosa), and in peripheral tissues. High levels of the receptor have been detected in the prefrontal cortex, periaqueductal gray, raphe nuclei (dorsal), ventral tegmental area, substantia nigra, dorsal striatum (putamen, caudate), ventral striatum (nucleus accumbens, olfactory tubercle), amygdala, bed nucleus stria terminalis, claustrum, hippocampus, hypothalamus, midline thalamic nuclei, locus coeruleus, spinal trigeminal nucleus, parabrachial nucleus, and solitary nucleus. 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 potently analgesic, and have been employed clinically in the treatment of pain. However, KOR agonists also produce side effects such as dysphoria, hallucinations, and dissociation, which has limited their clinical usefulness. Examples of KOR agonists that have been used medically as analgesics include butorphanol, nalbuphine, levorphanol, levallorphan, pentazocine, phenazocine, and eptazocine. Difelikefalin (CR845, FE-202845) and CR665 (FE-200665, JNJ-38488502) are peripherally restricted KOR agonists lacking the CNS side effects of centrally active KOR agonists and are currently under clinical investigation as analgesics. Centrally active KOR agonists have hallucinogenic or dissociative effects, as exemplified by salvinorin A (the active constituent in Salvia divinorum). These effects are generally undesirable in medicinal drugs. It is thought that the hallucinogenic and dysphoric effects of opioids such as butorphanol, nalbuphine, and pentazocine serve to limit their 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 lysergic acid diethylamide (LSD), psilocybin, or mescaline. The claustrum is the region of the brain in which the KOR is most densely expressed. It has been proposed that this area, based on its structure and connectivity, has 'a role in coordinating a set of diverse brain functions', and the claustrum has been elucidated as playing a crucial role in consciousness. As examples, lesions of the claustrum in humans are associated with disruption of consciousness and cognition, and electrical stimulation of the area between the insula and the claustrum has been found to produce an immediate loss of consciousness in humans along with recovery of consciousness upon cessation of the stimulation. On the basis of the preceding knowledge, it has been proposed that inhibition of the claustrum (as well as, 'additionally, the deep layers of the cortex, mainly in prefrontal areas') by activation of KORs in these areas is primarily responsible for the profound consciousness-altering/dissociative hallucinogen effects of salvinorin A and other KOR agonists. In addition, it has been stated that 'the subjective effects of S. divinorum indicate that salvia disrupts certain facets of consciousness much more than the largely serotonergic hallucinogen ', and it has been postulated that inhibition of a brain area that is apparently as fundamentally involved in consciousness and higher cognitive function as the claustrum may explain this. However, these conclusions are merely tentative, as ' are not exclusive to the claustrum; there is also a fairly high density of receptors located in the prefrontal cortex, hippocampus, nucleus accumbens and putamen', and 'disruptions to other brain regions could also explain the consciousness-altering effects '.