Κ-opioid receptor
The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, 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 among related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These include altering nociception, mood, reward system, and motor control.
KOR is one of the two opioid receptors that bind dynorphin opioid peptides as the primary endogenous ligands, the other being newly deorphanized GPR139 receptor. In addition, oxytocin was found to be a positive allosteric modulator of KOR, and a variety of natural alkaloids, terpenes and synthetic ligands bind to the receptor.
Dysregulation of this receptor system has been implicated in multiple psychiatric disorders including: depressive and anxiety disorders, disorders of diminished motivation, schizophrenia, borderline personality disorder, bipolar disorder, substance use disorder.
Ligands binding to the receptor have been approved the treatment of pruritus and pain management. Aside from those indications they are investigated for various psychiatric disorders, irritable bowel syndrome, and acute stroke.
Tissue distribution
Central nervous system
Brain
KORs are widely distributed throughout the brain. The claustrum represents the brain region with the highest density of KOR expression. Other CNS regions expressing moderate to high KOR densities include the prefrontal cortex, periaqueductal gray, dorsal raphe nuclei, ventral tegmental area, substantia nigra, dorsal striatum, ventral striatum, amygdala, bed nucleus of the stria terminalis, hippocampus, hypothalamus, thalamus, locus coeruleus, spinal trigeminal nucleus, parabrachial nucleus, and solitary nucleus.Positron emission tomography imaging studies with the KOR-selective radioligand GR-103545 in non-human primates showed high binding potential in the pituitary gland, followed by insula, claustrum, and orbitofrontal cortex, with moderate binding in nucleus accumbens, amygdala, and hippocampus. bremazocine binding showed elevated densities along the ventral edge of the nucleus accumbens and ventral putamen regions.
There is evidence that distribution and/or function of this receptor may differ between sexes.
Spinal cord
In spinal cord, KOR is expressed in the substantia gelatinosa and superficial laminae of the dorsal horn, where they modulate thermal nociception and chemical viscelar pain. They are concentrated in the upper laminae of the dorsal horn and within the posterolateral tract. The highest density was localized within the inner segment of lamina II, forming a dense band immediately dorsal to lamina III. 53% of KOR binding sites in the superficial dorsal horn are localized presynaptically on primary afferent terminals, with the remainder distributed postsynaptically.Peripheral nervous system
Dorsal root ganglia
KOR is present in dorsal root ganglia in moderate expression levels in human tissue. KOR is expressed in peptidergic primary afferents genes encoding calcitonin gene-related peptide and substance P, as well as in populations of low-threshold mechanoreceptors that innervate hair follicles. In human DRG neurons, approximately 25% cells express OPRK1 mRNA.Immune cells
In immune cells, KOR is distributed in specific leukocyte populations. Approximately 50% of resident peritoneal macrophages express KOR, while expression decreases during lymphocyte maturation, with less than 25% of splenic T-helper or T-cytotoxic lymphocytes and only 16% of splenic B lymphocytes displaying receptor expression.Gastrointestinal tract
In the gastrointestinal tract, KOR is expressed on myenteric and submucosal plexus neurons, where they modulate intestinal motility and secretion. Both KOR and MOR mRNAs are expressed in all investigated gastrointestinal regions in one study, with the stomach and proximal colon displaying the highest expression levels, and the duodenum exhibiting the lowest. KOR in the proximal colon represented 40% of the amount found in the brain. A higher number of neurons expressing KOR-like immunoreactivity are visualized in the myenteric plexus with a smaller number in the submucosal plexus, unlike the distribution pattern of MORs.Cardiovascular system
KORs are expressed in human cardiac tissue, including cardiomyocytes, where they exert negative inotropic and lusitropic effects through pertussis toxin-sensitive Gi/o protein signaling.Renal system
Healthy human kidney expresses KOR, yet detailed cellular localization within specific nephron segments aren't investigated.Subtypes
Based on receptor binding studies, three variants of the KOR: κ1, κ2, and κ3 have been characterized via radioligand binding and regional CNS mapping. However, only one encoding cDNA has been cloned, hence these subtypes likely arise from interactions of the KOR protein with other membrane-associated proteins rather than gene duplication. Historically the understanding that KORs are encoded by a single gene reopened the question of how one receptor system could be involved in such a multiplicity of interactions and disparate profiles.Function
General
KOR agonism seems to functionally oppose multiple effects mediated by μ-opioid receptors and δ-opioid receptors, including analgesia, tolerance, euphoria, and memory regulation. Activation of KOR by dynorphins during stress exposure has been shown to induce dysphoria, aversion, and negative affective states in both human and non-human subject. This contrasts with activation of MOR, which is associated with mood elevation and producing hedonic effects. Consequently, the KOR system has traditionally been conceptualized as mediating anti-reward processes and negative reinforcement, representing a functional counterpart to MOR in terms of behavioral and affective outcomes. However, recent research highlights a more nuanced role for KOR signaling, implicating it in a spectrum of complex behaviors and neural processes that extend beyond a strictly dichotomous and unidemensional frameworks, including functions independent of hedonic tone within reward processing.Centrally active KOR agonists have distinct, atypical dissociative hallucinogenic effects, as exemplified by salvinorin A. The experiences include: dissociation, incapacitation, psychotomimesis, profound alterations in interoception, somatic sensations, visual and auditory hallucinations, synesthesia, sedation, analgesia, anti-inflammation, neuroprotection, memory impairment, anti-addiction, aversion, dysphoria, anxiogeny, both antidepressant and depressogenic effect.
Signaling bias
Main section:Many functional differences between KOR agonists can be explained by biased signaling, whereby different agonists preferentially activate distinct signaling pathways downstream of the receptor. Evidence suggests that G protein signaling primarily mediates the therapeutic analgesic and antipruritic effects of KOR agonists, whilst β-arrestin2-dependent signaling through p38 MAPK activation mediates adverse dysphoric, sedative, and aversive effects.
Limitations
Studying the exact functions mediated by KOR is limited by the non-selectivity and signaling biases of the compounds used in the research and naturally occurring in the human body. Dynorphin peptides, endogenous agonists of KOR, especially big dynorphin, are direct complex modulators of the NMDA receptor. Certain dynorphin peptides also have affinity for the MOR and DOR and influence other pathways that are not directly coupled to KOR. KOR activation in the context of in vivo stress responses could be biased for β-arrestin2 and other pathways related to dysphoria due to the presence of corticotropin-releasing hormone. Salvinorin A as well as other KOR agonists have been found to possess properties such as dopamine D2 receptor agonism with lower, but non-negligible affinity and potency. Salvinorin A is a balanced G protein and β-arrestin2 agonist.Pain
Similarly to μ-opioid receptor, KOR activation produces antinociceptive effects. KOR agonists are potently analgesic and have been employed clinically for pain management, but they produce characteristic adverse effects which both limit their abuse potential and, unfortunately, their therapeutic utility.The receptor mediates acute thermal and mechanical pain processing. The anelgesic actions of KOR occur at both spinal and supraspinal sites. In the spinal cord, presynaptic activation suppresses nociceptive transmission through inhibition of calcium influx and reduction of neurotransmitter release from primary sensory neurons.
Neuropathic pain following peripheral nerve injury is accompanied by sustained elevation of dynorphin levels in the spinal dorsal horn, resulting in tonic KOR activation that contributes to pain inhibition. The prodynorphin-derived opioid system within the spinal cord exhibits both pronociceptive and antinociceptive functions. Acute KOR activation produces pain reversal and chronic stimulation leads to receptor tolerance and hyperalgesia with allodynia. Mechanisms such as activation of NMDA receptors on spinal interneurons, and increasing glutamate and substance P release from primary afferent terminals might play a role.
KOR also mediates the affective-motivational dimensions of pain. At the supraspinal level, KOR activation in the ventral tegmental area, periaqueductal gray, and other pain-modulatory nuclei influences both pain perception and pain-related motivated behavior. The engagement of KOR during chronic pain states, particularly neuropathic pain, has been implicated in the high comorbidity between chronic pain and mood disorders, as dynorphin-mediated KOR signaling in limbic and reward-related brain regions drives negative emotional states and anhedonia.