Function Κ-opioid receptor

1 function

1.1 pain
1.2 consciousness
1.3 mood, stress, , addiction
1.4 others

function
pain

similarly μ-opioid receptor (mor) agonists, kor agonists potently analgesic, , have been employed clinically in treatment of pain. however, kor agonists produce side effects such dysphoria, hallucinations, , dissociation, has limited clinical usefulness. examples of kor agonists have been used medically analgesics include butorphanol, nalbuphine, levorphanol, levallorphan, pentazocine, phenazocine, , eptazocine. difelikefalin (cr845, fe-202845) , cr665 (fe-200665, jnj-38488502) peripherally restricted kor agonists lacking cns side effects of centrally active kor agonists , under clinical investigation analgesics.

consciousness

centrally active kor agonists have hallucinogenic or dissociative effects, exemplified salvinorin (the active constituent in salvia divinorum). these effects undesirable in medicinal drugs. thought hallucinogenic , dysphoric effects of opioids such butorphanol, nalbuphine, , pentazocine serve limit abuse potential. in case of salvinorin a, structurally novel neoclerodane diterpene kor agonist, these hallucinogenic effects sought after, though experience considered dysphoric user. while salvinorin considered hallucinogen, effects qualitatively different produced classical psychedelic hallucinogens such lysergic acid diethylamide (lsd), psilocybin, or mescaline.

the claustrum region of brain in kor densely expressed. has been proposed area, based on structure , connectivity, has role in coordinating set of diverse brain functions , , claustrum has been elucidated playing crucial role in consciousness. examples, lesions of claustrum in humans associated disruption of consciousness , cognition, , electrical stimulation of area between insula , claustrum has been found produce immediate loss of consciousness in humans along recovery of consciousness upon cessation of stimulation. on basis of preceding knowledge, has been proposed inhibition of claustrum (as as, additionally, deep layers of cortex, in prefrontal areas ) activation of kors in these areas responsible profound consciousness-altering/dissociative hallucinogen effects of salvinorin , other kor agonists. in addition, has been stated subjective effects of s. divinorum indicate salvia disrupts facets of consciousness more largely serotonergic hallucinogen [lsd] , , has been postulated inhibition of brain area apparently fundamentally involved in consciousness , higher cognitive function claustrum may explain this. however, these conclusions merely tentative, [kors] not exclusive claustrum; there high density of receptors located in prefrontal cortex, hippocampus, nucleus accumbens , putamen , , disruptions other brain regions explain consciousness-altering effects [of salvinorin a] .

in supplementation of above, according addy et al.:

theories suggest claustrum may act bind , integrate multisensory information, or else encode sensory stimuli salient or nonsalient (mathur, 2014). 1 theory suggests claustrum harmonizes , coordinates activity in various parts of cortex, leading seamless integrated nature of subjective conscious experience (crick , koch, 2005; stiefel et al., 2014). disrupting claustral activity may lead conscious experiences of disintegrated or unusually bound sensory information, perhaps including synesthesia. such theories in part corroborated fact [salvia divinorum], functions exclusively on kor system, can cause consciousness decoupled external sensory input, leading experiencing other environments , locations, perceiving other “beings” besides in room, , forgetting oneself , one’s body in experience.

mood, stress, , addiction

the involvement of kor in stress, in consequences of chronic stress such depression, anxiety, anhedonia, , increased drug-seeking behavior, has been made clear. kor agonists notably dysphoric , aversive @ sufficient doses. kor antagonists buprenorphine, alks-5461 (a combination formulation samidorphan), , cerc-501 (ly-2456302) in clinical development treatment of major depressive disorder , substance use disorders. jdtic , pf-4455242 under investigation development halted in both cases due toxicity concerns.

the depressive-like behaviors following prolonged morphine abstinence appear mediated upregulation of kor/dynorphin system in nucleus accumbens, local application of kor antagonist prevented behaviors. such, kor antagonists might useful treatment of depressive symptoms associated opioid withdrawal.

in small clinical study, pentazocine, kor agonist, found rapidly , substantially reduce symptoms of mania in patients bipolar disorder. postulated efficacy observed due kor activation-mediated amelioration of excessive dopaminergic signaling in reward pathways.

others

a variety of other effects of kor activation known:

activation of kor appears antagonize many of effects of mor, including analgesia, tolerance, euphoria, , memory regulation. nalorphine , nalmefene dual mor antagonists , kor agonists have been used clinically antidotes opioid overdose, although specific role , significance of kor activation in indication, if any, uncertain. in case however, kor agonists notably not affect respiratory drive, , hence not reverse mor activation-induced respiratory depression.
kor agonists suppress itching, , selective kor agonist nalfurafine used clinically antipruritic (anti-itch drug).
eluxadoline peripherally restricted kor agonist mor agonist , dor antagonist has been approved treatment of diarrhea-predominant irritable bowel syndrome. asimadoline , fedotozine selective , peripherally restricted kor agonists investigated treatment of irritable bowel syndrome , reportedly demonstrated @ least efficacy indication never marketed.
kor agonists known characteristic diuretic effects, due negative regulation of vasopressin, known antidiuretic hormone (adh).
kor agonism neuroprotective against hypoxia/ischemia.
the selective kor agonist u-50488 protected rats against supramaximal electroshock seizures, indicating kor agonism may have anticonvulsant effects.




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