Inspinal cord, KOR is expressed in thesubstantia gelatinosa and superficial laminae of thedorsal horn, where they modulate thermalnociception and chemicalviscelar pain.[22][35] They are concentrated in the upper laminae of the dorsal horn (laminae I–III) and within theposterolateral tract.[35] The highest density was localized within the inner segment of lamina II, forming a dense band immediately dorsal to lamina III.[35][36] 53% of KOR binding sites in the superficial dorsal horn (laminae I–II) are localizedpresynaptically on primaryafferent terminals, with the remainder distributedpostsynaptically.[37]
Myenteric plexusperikarya of the rat stomach and colon areimmunoreactive for KOR, with numerousnerve fibers distributed in the longitudinal and circular muscle layers, whereassmooth muscle cells lack receptor immunoreactivity.[42][43] A higher number of neurons expressing KOR-like immunoreactivity are visualized in the myenteric plexus with a smaller number in thesubmucosal plexus, unlike the distribution pattern of MORs.[43]
Based onreceptor binding studies, three variants of the KOR: κ1, κ2, and κ3 have been characterized viaradioligand binding and regionalCNS mapping.[49][50] However, only one encodingcDNA has been cloned.,[51] hence these subtypes likely arise from interactions of the KORprotein with othermembrane-associated proteins rather thangene duplication.[52] 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.[53]
KORagonism seems to functionally oppose multiple effects mediated byμ-opioid receptors (MOR) andδ-opioid receptors (DOR), includinganalgesia,tolerance,euphoria, andmemory regulation.[54] Activation of KOR bydynorphins duringstress exposure has been shown to inducedysphoria,aversion, and negativeaffective states in both human and non-human subject.[55][56] This contrasts with activation of MOR, which is associated withmood elevation and producinghedonic effects.[57][58] Consequently, the KOR system has traditionally been conceptualized as mediatinganti-reward processes andnegative reinforcement, representing a functional counterpart to MOR in terms of behavioral and affective outcomes.[59][60] 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 ofhedonic tone within reward processing.[53][61][62][63]
Many functional differences between KOR agonists can be explained bybiased signaling, whereby different agonists preferentially activate distinctsignaling pathways downstream of the receptor.[67][68][69] Evidence suggests thatG protein signaling primarily mediates the therapeutic analgesic andantipruritic effects of KOR agonists, whilstβ-arrestin2-dependent signaling throughp38 MAPK activation mediates adverse dysphoric, sedative, and aversive effects.[59][70]
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 occuring in the human body.[69] Dynorphinpeptides,endogenous agonists of KOR, especiallybig dynorphin, are direct complex modulators of theNMDA receptor.[69] Certain dynorphin peptides also have affinity for the MOR and DOR and influence other pathways that are not directly coupled to KOR.[71][53] KOR activation in the context ofin vivo stress responses could be biased for β-arrestin2 and other pathways related to dysphoria due to the presence ofcorticotropin-releasing hormone (CRF).[12][72] Salvinorin A as well as other KOR agonists have been found to possess properties such asdopamine D2 receptor agonism with lower, but non-negligibleaffinity andpotency.[73][74] Salvinorin A is a balancedG protein and β-arrestin2 agonist.[75][76]
Neuropathic pain followingperipheral 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.[80] Theprodynorphin-derived opioid system within the spinal cord exhibits bothpronociceptive and antinociceptive functions. Acute KOR activation produces pain reversal and chronic stimulation leads to receptortolerance and hyperalgesia withallodynia. Mechanisms such as activation ofNMDA receptors onspinal interneurons, and increasing glutamate and substance P release from primary afferent terminals might play a role.[80]
KOR exhibits coexpression withoxytocin andvasopressin in theparaventricular nucleus (PVN) andsupraoptic nucleus (SON) of the hypothalamus.[92][93][94] Functional KORs are present onnerve terminals of both oxytocin and vasopressin neurons in the ratneurohypophysis, where agonists inhibitpotassium-evoked hormone release.[95] Both dynorphin-(1-8) and -(1-17) suppress stimulated oxytocin release from isolatedneurosecretory endings, with effects on the initial and secondary peaks of hormone secretion, while exerting no influence on vasopressin release under similar conditions.[96][97] These interactions extend to plasma hormone levels, where KOR agonists decrease circulating oxytocin concentrations, whileantagonists increase oxytocin release, suggesting that KOR signaling mediates negative regulation of oxytocinsecretion duringstress or physiological challenges.[97][98]
Diverse stressors initiate CRF release which subequently leads to dynorphin release and KOR activation inlimbic circuits. This integrated stress response is mediated primarily bycorticotropin-releasing factor (CRF), one of the mainneuropeptide integrators of the stress response.[12][98][100]
Acutely stress-induced dynorphin release and KOR activation have evolutionarily adaptive functions. KOR-mediatedanalgesia facilitates physical escape responses to threat and concurrent KOR-induced dysphoria and aversion promoteavoidance and active coping. However, during the delayed temporal phase following acute stress exposure (hours to days), stress-induced KOR signaling initiatesintracellular signaling cascades includingp38 MAPK andextracellular signal-regulated kinases (ERK) which phosphorylatetranscription factors such ascAMP response element-binding protein (CREB) and alter dynorphin and KORgene expression itself, establishing a self-amplifying cycle.[111]
Chronic social defeat stress produces a counterintuitive long-lastingdownregulation ofprodynorphinmRNA levels in the NAcc (occurring by day 10 of chronic exposure), and this downregulation is reversed by chronic treatment with standardantidepressant medication (imipramine).[112] Despite this molecular downregulation, behavioral signs of stress-induced dysphoria, anhedonia, and anxiety persist and even intensify with repeated stress exposure, indicating that the coupling between dynorphin release and KOR phosphorylation, as well as the downstream consequences of KOR activation, may become sensitized through counter-adaptations in post-receptor signaling or in competing inhibitory circuits.[112] This process involves:§ Signaling after internalisation.
KOR activation suppressesserotonergic tone through multiple mechanisms, including regulation of theserotonin transporter (SERT). Dynorphin, released from local GABAergic neurons within reward-related regions, binds to KORs expressed on serotonergic terminals projecting from the DRN to regions including such as NAcc,prefrontal cortex, and other limbic structures associated with mood regulation, reducing the availability of serotonin to activatepostsynaptic5-HT1A receptors in these targets.[113][114][115]Agonist-induced binding to these receptors triggers rapid,concentration-dependent downregulation of SERT function throughCaMKII andAkt.[116][117] This downregulation occurs through increased internalization of SERT from theplasma membrane viadynamin-dependentendocytosis, coupled with increased phosphorylation of thetransporter protein, reducing its functional availability and depressing serotonergicneurotransmission in hedonic circuits.[116] Under conditions of chronic stress, sustained KOR-mediated suppression could result in blunted responsiveness of postsynaptic neurons to residual serotonin, effectively rendering them hyporesponsive.[56][118]
In the NAcc, stress-dependent upregulation of postsynaptic5-HT1B receptors co-expressed ondirect pathway neurons expressing prodynorphin is an additional downstream mechanism. 5-HT1B receptor, also coupled toGi/o proteins, mediates serotonin-dependent inhibition ofdopaminergic neuronexcitability and modulate the balance between reward approach andbehavioral inhibition. Chronic stress-induced elevation of 5-HT1B expression in these accumbens neurons paradoxically increases sensitivity todopamine suppression and amplifies the anhedonic phenotype despite the simultaneous reduction in baseline serotonin availability.[119]
Themesolimbic dopaminergic circuit functions as a substrate for KOR-regulated mood homeostasis.[20][120]Dynorphin is synthesized and released bydopamine D1 receptor-expressingmedium spiny neurons within the NAcc, establishing a localnegative feedback loop that suppressesdopamine release.[121] KOR activation on dopamine terminals inhibits dopamine release through multiple mechanisms: increasedpotassium conductance viaG protein-coupledinward-rectifier potassium (GIRK) channels, suppression ofcalcium entry, activation ofprotein kinase C-β (PKCβ),c-Jun N-terminal kinase (JNK), and ERK,[122] as well as facilitation ofdopamine transporter (DAT) function through ERK1/2-dependent pathways that accelerate dopamine reuptake.[123] Additionally, KOR activation on local dynorphin-expressing neurons produces presynaptic inhibition of both glutamatergic and GABAergic afferents onto D1 receptor-expressing medium spiny neurons, with preferential suppression of amygdala inputs to D1-MSNs while facilitating integration of hippocampal/amygdalar inputs onto D2 receptor-expressing neurons through disinhibition.[124]
In the caudal NAcc shell, KOR-induced dopamine suppression triggersanxiogenic behaviors accompanied by reducedlocomotor activity.[125] Conversely, in the rostral shell, KOR activation produces attenuated dopaminergic suppression with diminished aversive behavioral consequences.[126] This topographic architecture extends to the NAcc core, where KOR-mediated dopamine inhibition similarly manifests with greater intensity in the caudal relative to rostral subregion.[127] The DRN to ventral tegmental area (VTA) circuit is an additional stress-responsive pathway whereby prodynorphin-expressing neurons release dynorphin at dopaminergic terminals, enabling KOR-dependent suppression of dopamine neuron excitability during acute stressors.[122][126][127][128]
The KOR system is involved in increaseddrug-seeking behavior.[12] KORagonists have been investigated for their therapeutic potential in the treatment of addiction.[129] and evidence points towardsdynorphinpeptides, theendogenous KOR agonists, to be the body's natural addiction control mechanism.[130]Childhood stress andabuse are well-known predictors ofdrug abuse which is reflected in alterations of the MOR and KOR systems.[131] In experimental "addiction" models the KOR has also been shown to influence stress-inducedrelapse 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 ofcocaine seeking.[132][133]
Thenucleus accumbens (NAcc) and broaderstriatum are among the brain regions most strongly associated with addiction, although other structures that project to and from the NAcc also play critical roles in addictive processes. Though many other changes occur, addiction is often characterized by the reduction in the availability ofdopamine D2 receptors in the NAcc.[134] In addition to decreasing NAcc D2 binding,[135][136] cocaine is also known to produce a variety of changes to theprimate brain such as increases ofprodynorphinmRNA in caudate putamen and decreases of the same polypeptide in thehypothalamus. The administration of a KOR agonist produced an opposite effect, causing an increase in D2receptor availability in the NAcc.[137]
Additionally, while cocaineoverdose victims showed a large increase in KORs (doubled) in the NAcc,[138] KOR agonist administration is shown to be effective in decreasing cocaine seeking and self-administration.[139] Furthermore, while cocaine abuse is associated with loweredprolactin response,[140] KOR activation causes a release of prolactin,[87] ahormone known for its important role in learning,neuronal plasticity andmyelination.[141]
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.[142][143] 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 fromhomeostasis toallostasis. It has been suggested thatwithdrawal-induceddysphoria or stress-induced dysphoria may act as a driving force by which the individual seeks alleviation via drug taking.[144] The rewarding properties of drug are altered, and it is clear KOR activation following stress modulates thevalence 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 ondopamine systems are well documented, and recent work also implicates thep38 MAPK cascade and pCREB in KOR-dependent behaviors.[145][111]
The anti-rewarding properties of KOR agonists are mediated through both chronic and acute effects. The immediate effect of KOR agonism leads to reduction ofdopamine release in the NAcc during self-administration of cocaine[151] and over the chronic period upregulates receptors that have been downregulated during substance abuse such as the MOR and the D2 receptor. These receptors modulate the release of otherneurochemicals such asserotonin in the case of MOR agonists, andacetylcholine 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, ornorepinephrine and/or via activation of downstreamsignal transduction pathways.
Of significant note, while KOR activation blocks many of the behavioral and neurochemical responses elicited by drugs of abuse as stated above. These results are indicative of the KOR induced negative affective states counteracting the rewarding effects of drugs of abuse. Implicating the KOR/dynorphin system as an anti-reward system, supported by the role of KOR signaling and stress, mediating both stress-induced potentiation of drug reward and stress-induced reinstatement of seeking behavior.[20][102] This in turn addresses what was thought to be paradoxical above. That is, rather, KOR signaling is activated/upregulated by stress, drugs of abuse and agonist administration - resulting in negative affective state. As such drug addiction is maintained by avoidance of negative affective states in stress, craving, and drug withdrawal.[152] Consistent with KOR induced negative affective states and role in drug addiction, KOR antagonists are efficacious at blocking negative affect induced by drug withdrawal and at decreasing escalated drug intake in pre-clinical trial involving extended drug access.[20][146][102]
Traditional models of KOR function in drug addiction have postulated that KOR signaling is associated with dysphoria andaversion, thought to underlie the stress-induced exacerbation of addiction. However, recent research in animal models has proposed alternative models, suggesting that KOR-mediated responses may not act directly on negative valence systems but modulate related processes such as novelty processing.[153][154] Studies in humans came to similar conclusions that KORs may modulate various aspects of reward processing in a manner that is independent of the hedonic valence traditionally ascribed to them.[14][155] This broadens the potential understanding of KORs in addiction beyond a unidimensional framework, implicating their role in complex behaviors and treatment approaches that do not align strictly with stress or aversion. These emerging perspectives may inform the development of novel pharmacotherapies targeting KORs for the treatment ofsubstance use disorders, as they highlight the receptor's multifaceted role in addiction.
Theclaustrum is the region of thebrain in which the KOR is most densely expressed.[24][26][156] Historically, it has been proposed on the basis of the claustrum's structural and connectivity characteristics that this region orchestrates diverse brain functions and serves as a critical substrate forconsciousness.[24][26] Clinical observations supported this hypothesis:lesions of the claustrum in humans are associated with disruption of consciousness andcognition, andelectrical stimulation of theinsula-claustrum border has been found to produce immediate loss of consciousness in humans, with recovery upon cessation of stimulation.[26][157] Earlier theories 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 atypicaldissociativehallucinogen effects ofsalvinorin A and other KORagonists.
Theories suggest the claustrum may act to bind and integrate multisensory information, or else to encode sensory stimuli as salient or nonsalient (Mathur, 2014). One theory suggests the claustrum harmonizes and coordinates activity in various parts of the cortex, leading to the seamless integrated nature of subjective conscious experience (Crick and Koch, 2005; Stiefel et al., 2014). Disrupting claustral activity may lead to conscious experiences of disintegrated or unusually bound sensory information, perhaps including synesthesia. Such theories are in part corroborated by the fact that [salvia divinorum], which functions almost exclusively on the KOR system, can cause consciousness to be decoupled from external sensory input, leading to experiencing other environments and locations, perceiving other "beings" besides those actually in the room, and forgetting oneself and one's body in the experience.
From this perspective, disrupting claustral activity might lead to conscious experiences of disintegrated or unusually bound sensory information, includingsynesthesia.[156] However, even early formulations acknowledged that their assumptions are merely tentative and that "KORs are not exclusive to the claustrum; there is also a fairly high density of receptors located in theprefrontal cortex,hippocampus,nucleus accumbens andputamen", and that "disruptions to other brain regions could also explain the consciousness-altering effects [of salvinorin A]".[26]
The task of elucidating the exact role of claustrum in mediating sensory information and conscioussness remains a topic of active debate.[158] And findings on whether distruptions of claustral activity lead to the loss of consciousness are conflicting.[26][159][160][161]
Recent imaging studies have confirmed the suspected complexity and multi-regional character of specifically KOR-mediated alterations, and argued that the neural substrates involvecortico-thalamic integration anddefault mode network (DMN) disruption rather than claustrum-centric mechanism.[65] Salvinorin A induces decreases in default mode network connectivity, specifically within the medial prefrontal cortex andposterior cingulate cortex and increased between-network connectivity with reduced dynamic connectivity stability.[65] While both salvinorin A andpsilocybin attenuate default mode network connectivity, their effects on thalamocortical networks differ; salvinorin A-induced thalamic modulation is independent of5-HT2A receptor activation.[162]
Thethalamus, especially thecentromedian,paraventricular, andcentrolateral nucleus, expresses high KOR density and mediates corticalarousal, viscero-limbic integration, and relay of sensory andinteroceptive information to cortical processing hierarchies. KOR activation within these thalamic nuclei reduces the relay ofexteroceptive andinteroceptive information to the cortex, producing the characteristic dissociation from external reality and loss of contact withself-representation andbody schema.[64][65] Salvinorin A induces prominentauditory phenomena and gating of audio-visual information at the perceptual threshold, coupled with unusual modifications of interoceptive awareness and body ownership that exhibit inverted-U-shapeddose-response relationship. Low to moderate doses enhance sensations and perceived body-safety, whereas high doses producedepersonalization, loss of body awareness,out-of-body experiences, and subjective feelings of existing in alternative spatial or dimensional realities, sometimes as objects or alternatively otherliving organisms.[65]
KOR activation also suppresses activity in sensory-integration regions, includingparietal andtemporal areas involved in body schema codification and multisensory binding, whilst simultaneously disrupting medial prefrontal cortex-mediated self-referential processing within the DMN.[64] The claustrum is embedded within cortico-claustro-cortical loops that depend on maintained thalamic-cortical communication; consequently, thalamic KOR activation may disrupt claustral function indirectly through compromisedafferent andefferent signaling rather than through direct local inhibition.[162] Collectively, it is likely that KOR-mediated experiences of dimensionality alterations, synesthesia, and modified temporal perception represent emergent properties of disrupted hierarchical sensory integration at thalamic and cortical levels coupled with claustrum activity rather than direct consequences of that single region or modulation of its pathways.[65][162]
Peripheral KOR activation drives sensory responses including coldallodynia and mechanical hypersensitivity through mechanisms distinct fromcentral effects.[77]
Single nucleotide polymorphisms (SNPs) genetic variations withinOPRK1, have been associated with susceptibility tosubstance use disorders andstress-related behaviors. The G36T SNP (rs1051660) is more frequent inheroin-dependent individuals compared to healthy controls.[190] Other study found an association ofOPRK1 variants withcocaine dependence andrelapse susceptibility.[191]
Postmortem samples fromsuicide completers with a history of severechild abuse (CA) had higher rates of KOR downregulation relative to controls and suicide completers without CA history, an effect not accompanied by alterations in multiple other genes.[192] Hypomethylation ofOPRK1 intron 2 was associated with the CA group, as low levels ofDNA methylation facilitateglucocorticoid binding and subsequent regulation ofOPRK1transcription. Additionally, a specific insertion deletion (INDEL)polymorphism, rs35566036, in theOPRK1promoter region occurred more frequently in suicide completers withmajor depressive disorder relative to healthy controls.[192]
Similar epigenetic alterations inOPRK1 methylation patterns have been linked toborderline personality disorder (BPD), where an imbalance between opioid receptor systems could cause symptoms such as chronicdysphoria,suicidality, and emotional instability.[17][193][194] In individuals with BPD, decreased DNA methylation (hypomethylation) in a differentially methylated region (DMR) located within thepromoter region, specifically at a cluster of five adjacentCpG sites (CG34–CG38) positioned immediately upstream of core CpG islands (CGI-1 and CGI-2), results in enhancedgene transcription and elevated KOR expression.[17]
The DMR hypomethylation in BPD is strategically positioned on the "falling slope" of the gene's methylation gap; a transition zone between the sparsely methylated CpG island promoter and densely methylated downstream regions. This location amplifies the functional consequences of hypomethylation by progressively steepening the methylation gradient, further facilitating transcription initiation at multiple transcription start sites (TSS) distributed throughout the CGI promoter region. Consequently, the decreased methylation rates in the DMR are associated with increasedOPRK1 mRNA transcription and heightened KORprotein expression in peripheralwhite blood cells and, by extension, in central brain regions involved inemotion regulation.[17]
Symptom severity in BPD correlates with DMR hypomethylation levels. As DMR methylation rates decrease (become more hypomethylated), BPD symptom severity measured by the Borderline Symptom List (BSL-23) increases. Additionally, heightened traitimpulsivity, measured by theBarratt Impulsivity Scale, and particularly its motor impulsivity subscale, showsinverse relationships with DMR methylation levels.[17]
The epigenetic imbalance may also impact social attachment and interpersonal functioning through effects onmu-opioid receptor (MOR).Childhood neglect produces chronic basal understimulation of MORs, which mediatereward and socialmotivation. Paradoxically, prolonged MOR understimulation may trigger compensatory MORupregulation in regions such as theamygdala andorbitofrontal cortex. This MORhypersensitization, with its heightened responsivity to negative affective stimuli, may in turn provoke strong counter-activating KOR responses, resulting in the increasedOPRK1 expression observed epigenetically. This KOR-MOR imbalance, where relative KOR overactivity combines with contextually inappropriate MOR hyperexcitability, likely affects BPD's dysregulation of interpersonal relationships and affective instability.[17]
Cocaine andmethamphetamine exposure induce epigenetic modifications of theOPRK1 andPDYN loci through both histone remodeling and DNA methylation pathways.[196] Acute cocaine and methamphetamine increasehistone H4acetylation andhistone acetyltransferase (HAT) activity in thestriatum, facilitating increasedPDYN andOPRK1 transcription that initiatesdynorphin-mediated counter-inhibition ofdopamine release.[196] This acute epigenetic activation could be interpreted as a compensatory mechanism attempting to restore dopaminergic homeostasis during drug-induced dopaminergic overstimulation.
In chronic context cocaine and methamphetamine exposure reverse this epigenetic profile through increasedDNA methyltransferase (DNMT) activity andhistone deacetylase (HDAC)-mediated repression of plasticity genes, including decreasedOPRK1 transcription.[196] Epigenetic silencing of adaptability genes consolidates compulsive drug-seeking behaviour whilst simultaneously dysregulating the KOR-mediated feedback system, facilitating withdrawal-related dysphoria and relapse vulnerability.[197]
Age-related changes inOPRK1 gene expression were observed in mousegastrointestinal tract, with mRNA expression significantly decreased in the distalileum in 12-month-old mice compared to 6-month-old animals, though nostatistically significant differences were detected in the stomach and colon.[199] Protein expression of dynorphin in the colon was lower in older mice.[199]
Repeated stress produces dynorphin-dependent activation of both KOR and p38 MAPK withinGABAergic neurons localized to the nucleus accumbens, prefrontal cortex, and hippocampus.[111] This p38 activation is dependent uponG protein-coupled receptor kinase 3 (GRK3) andβ-arrestin2 recruitment and occurs through Ser369 phosphorylation of KOR itself. Inhibition of p38 MAPK selectively blocks stress-induced immobility and conditioned place aversion while preserving analgesia and non-selective learning processes, isolating p38 signaling as specifically responsible for dysphoric-like behavioral responses.[111]
Evidence suggests that G protein signaling mediates the therapeuticanalgesic andantipruritic effects of KOR agonists, whilst β-arrestin2-dependent signaling through p38 MAPK activation mediates adversedysphoric,sedative, andaversive effects.[59][111] Experiments in β-arrestin2knockout mice demonstrated that theantipruritic effects of KOR agonists are preserved in the absence of β-arrestin2, whilstconditioned place aversion requires both GRK3 and β-arrestin2.[56][226]
In cells coexpressingorexin receptor 1 (OX1) and KOR, OX1 activation attenuates KOR-mediated Gαi inhibition of cAMP but increases β-arrestin2 recruitment and p38 activation via a JNK-dependent pathway, shifting KOR signaling toward non-G protein pathways. This unidirectional crosstalk promotes preferential β-arrestin/p38 signaling over Gαi, without affecting KOR ligand binding or OX1 Gαq coupling.[227]
Other study have implicatedprotein kinase C (PKC) in regulating behavioral responses and signaling pathways.[229] PKC inhibition maintains the analgesic and antipruritic properties of KOR agonists whilst reducing adverse effects including conditioned place aversion,anxiogenesis, and motor incoordination. At 5 minutes following KOR activation, PKC regulates GRK5/6 andWnt signaling pathways, whilst at 30 minutes PKC influences mTOR pathways andcannabinoid receptor 1.[229]
Simulations identified three distinct active-stateconformational states of KOR: the canonical active state, an alternative state, and an occluded state.[69] The alternative state, characterized by specifictransmembrane domain conformations, correlates withβ-arrestin2-biased signaling. The occluded state, in which the intracellular portion oftransmembrane helix 7 rotates clockwise towardtransmembrane helix 2, appears to favorG protein coupling whilst disfavoring β-arrestin recruitment.[69]
Specific residues within the receptorbinding pocket differentially influence G protein versus β-arrestin signaling. Disruption of the ionic interaction by certain agonists increases the distance between the extracellular ends of transmembrane helices 5 and 6, contributing to ligand-specifictransducer coupling preferences.[69]
KOR undergoes agonist-mediated GRK-dependent phosphorylation followed by β-arrestin recruitment, initiatingclathrin-mediatedendocytosis.[230] KOR trafficking differs compared to otheropioid receptors. Whereas theμ-opioid receptor (MOR) contains aC-terminal LENL recycling motif that engagesretromer complexes for rapid plasma membrane recycling, and theδ-opioid receptor (DOR) undergoes predominantlylysosomal degradation followinginternalization, KOR requires aPDZ domain-binding sequence for post-endocytic sorting.[231] Following internalization, KOR rapidly accumulates in earlyendosomes, where it remains partially dissociated from β-arrestin, allowing continued G protein coupling and signaling in compartment-specific contexts.[231]
KOR-mediated signaling persists within late endosomes and lysosomes despite agonist-induced translocation from the plasma membrane, representing a form of sustained "post-internalization" signaling distinct from plasma membrane coupling.[232]Dynorphin A maintains prolonged adenylyl cyclase suppression when KOR is sequestered within late endosomal and lysosomal compartments, which suggests that dynorphin isoforms differentially stabilize intracellular receptor conformations suited to late-compartment signaling.[230] This property distinguishes KOR from MOR, which primarily signals from endosomal compartments when β-arrestin-bound, and from classical recycling receptors that rapidly regain surface expression. The intracellular KOR signaling axis involves continued Gi/o coupling on late endosomal membranes, sustained suppression of adenylyl cyclase and cAMP production, and prolonged recruitment ofERK pathway components through Gβγ-dependent mechanisms, thereby establishing abiochemical niche for chronic dynorphin signaling distinct from acute plasma membrane responses.[232] This signaling permits differential integration of intracellular second messenger systems and transcriptional responses compared to plasma membrane-restricted coupling.[233]
Nalorphine andnalmefene are dual MORantagonists and KOR agonists used clinically asantidotes for opioidoverdose, but the specific role of KOR activation to their efficacy remains uncertain as KOR agonists do not reverserespiratory depression induced by MOR activation and thus cannot serve as standalone antidotes for this purpose.[235]
Peripherally selective KOR agonists display analgesic efficacy mediated throughanti-inflammatory effects onimmune cells andnociceptors.[236]CR665 anddifelikefalin (CR845, FE-202845) have been investigated clinically; marking the first peripherally-restricted KOR agonist to reach regulatory approval, though none have yet been approved specifically for pain indication.[237][238][239] Recent evidence supports the therapeutic potential of mixed KOR/MOR agonists and KOR-biased ligands as adjuncts to conventional analgesics in inflammatory andcancer pain, with particular promise for chronicneuropathic pain syndromes.[234]
The mechanistic rationale for KORantagonism inmajor depressive disorder (MDD) derives from the observation thatchronic stress anddepression are associated with higher activity of the KOR system.[18][240] KOR activation suppressesdopamine release and prevents dopamine rebound after stress exposure, thereby leading toanhedonia and depressive phenotypes. KOR antagonists reverse this pathway by disinhibiting dopaminergic tone and restoring reward sensitivity.[13][72][132][241] KOR-mediated upregulation ofpro-inflammatory signaling inmicroglia likely drives the depression pathophysiology, and antagonism may provide benefits.[241]
The persistent signaling that is present after internalisation could be the reason for ineffectivity of common KOR antagonists given that they work on receptor's outer membrane.[232] Antagonists also tend to preserves conformation states; in this case presumably "alternative state" due to the endogenous bias for theβ-arrestin signaling during stress responses.[69]
KOR antagonists have demonstratedanxiolytic efficacy inpreclinical stress models and early clinical evaluation. Early generation antagonists such asJDTic andnor-BNI produced anxiolytic-like effects inGAD,PTSD, andpanic disorder models. However their long duration of action and off-target toxicities limited clinical development.[164][242][247] Contemporary short-acting antagonists such as aticaprant are being evaluated for anxiety indications given their improved pharmacokinetic profiles and reduced toxicity burden.[245]
Persistent KOR signaling has been implicated in thepathophysiology ofschizophrenia, in the generation of both positive and negative symptoms, and as an explanation for treatment-resistantpsychosis.[15] Mechanistically, chronic KOR activation produces long-term sensitization ofdopamine D2 receptors in thestriatum, which manifests as supersensitized D2 receptor states that amplify phasic dopamine signaling and hyperresponsivity to dopaminergic stimuli.[248][249] This mechanism could interact with the underlying excessivestriatal dopamine transmission in schizophrenia, potentiating positive symptoms includingdelusions andhallucinations, and explaining whydopamine D2 receptor antagonists (antipsychotics) remain effective. Apart from striatal mechanisms, KOR signaling modulates corticalglutamate andGABAhomeostasis through KOR activation onGABAergic terminals ofdynorphin-expressing neurons inprefrontal cortex which suppresses GABA release and disrupting the balance of cortical inhibition-excitation that might drivecognitive dysfunction and negative symptoms.[249] Thus, KOR antagonism may provide a complementary strategy to D2 antagonism by simultaneously reducing D2 receptor sensitization to normalize striatal dopamine responsivity and restoring cortical inhibition-excitation balance to ameliorate cognitive dysfunction.[15][249]
Recent epigenetic findings suggest that KOR antagonists, which block the hyperactive KOR system, might be a viable pharmacological approach forborderline personality disorder (BPD) treatment, particularly for anhedonia, suicidality, and dissociative symptoms. Current early evidence supports the efficacy ofnaltrexone andnalmefene in reducing suicidal ideation, non-suicidalself-injury,binge eating, and dissociation in patients with BPD.[17][194]
In a small clinical study, pentazocine, a KOR agonist, rapidly reduced acutemanic symptoms inbipolar disorder patients.[18] The therapeutic mechanism is postulated to involve KOR agonist-mediated suppression of excessivedopaminergic signaling inreward pathways and striatal circuits that drive manic hyperactivity and impulsivity.[18] Complete desensitization of KOR renders the receptor unable to gate dopaminergic signaling, thereby lifting the inhibitory constraint and disinhibiting phasic dopamine andnorepinephrine release. Temporary KOR sensitization during acute mania may reverse this disinhibition.[232]
Aticaprant was well-tolerated incocaine use disorder (CUD) patients.[250] Apositron emission tomography (PET) study in CUD patients utilizing a KOR selective agonist [11C]GR-103545radioligand showed CUD individuals with higher KOR availability were more prone to stress-induced relapse.[251] A subsequent PET scan following a three-day cocaine binge showed a decrease in KOR availability, interpreted as increased endogenous dynorphin competing with the radioligand at the KORbinding sites.[251] These findings are in support of the negative affect state and further implicate the KOR/dynorphin system clinically and therapeutically relevant in humans with CUD. Taken together, in drug addiction the KOR system is implicated as a homeostatic mechanism to counteract the acute effects of drugs of abuse. Chronic drug use and stress up-regulate the system in turn leading to a dysregulated state which induces negative affective states and stress reactivity.[102]
KOR agonists have also been investigated for their therapeutic potential in the treatment ofaddiction, particularlysubstance use disorders.Ibogaine, atypical KOR agonist withG-protein-biased signaling and complex pharmacodynamics involving multiple neurotransmitter systems.[252] Ibogaine's primary active metabolite,noribogaine, acts as a moderate KOR agonist selective for G protein and a potentserotonin reuptake inhibitor.[252] This mechanism, combined with activity at5-HT2A,5-HT2C,σ2, andNMDA receptors, likely leads its anti-addictive effects.[253] The precise extent to which KOR agonism underlies ibogaine's anti-addictive properties is unclear.[252]
In animal models, ibogaine administration has been shown to reduceself-administration ofopioids,stimulants, andalcohol, amelioratewithdrawal symptoms, and decrease drug-seeking behavior.[254][255] A 2022systematic review of 24 studies involving 705 participants found that both ibogaine and noribogaine show promise in treating substance use disorders and comorbid depressive symptoms.[252]
In a mouse model, agonism of inhibitory, GABAergic KOR-containing neurons in therostral ventromedial medulla activates a top-down mechanism of inhibiting pain and itch perception from the spinal cord simultaneously.[258]
Eluxadoline is a peripherally restricted KOR agonist as well as MOR agonist and DOR antagonist that has been approved for the treatment ofdiarrhea-predominantirritable bowel syndrome.Asimadoline andfedotozine are selective and similarly peripherally restricted KOR agonists that were also investigated for the treatment of irritable bowel syndrome and reportedly demonstrated at least some efficacy for this indication but were ultimately never marketed.[23]
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