Disease relevance of OPRK1

• We report herein the presence of kappa opioid receptors (KORs) in human fetal microglia and inhibition of HIV-1 expression in acutely infected microglial cell cultures treated with KOR ligands [1].
• This mechanism-based finding provides functional evidence in support of the clinical potential of KOR agonists as antipruritics in the presence of MOR agonist-induced pruritus [2].
• To achieve a high density of receptors, replication-defective adenovirus (rAd5) vectors encoding the mu (MOR) and kappa (KOR) opioid receptors, both in their native form and as fusion proteins bearing the green fluorescent protein (GFP) at their C-terminus, were constructed [3].
• CONCLUSIONS/INTERPRETATION: Using selective peripheral KOR agonists to take advantage of elevated peripheral KOR expression may provide a novel therapeutic approach for painful diabetic neuropathy [4].
• Exploiting the presence and elevated levels of KOR in the periphery, we investigated the effect of the peripheral KOR agonist asimadoline on formalin-evoked hyperalgesia and tactile allodynia in diabetic rats [4].

Psychiatry related information on OPRK1

• Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction [5].
• This study: (i) characterized the genomic structure of the hOPRK1 gene; (ii) identified single nucleotide polymorphisms (SNPs) in the hOPRK1 gene; and (iii) investigated possible associations of these variants with vulnerability to develop heroin addiction [5].
• BACKGROUND: Nonselective opioid antagonists reduce alcohol consumption under various experimental situations, and several association studies have examined possible roles of opioid receptor mu (OPRM), delta (OPRD), and kappa (OPRK) genes in the development of alcohol dependence [6].
• Based on the selectivity of salvinorin A for the KOR, this receptor represents a potential molecular target for the development of drugs to treat disorders characterized by alterations in perception, including schizophrenia, Alzheimer's disease and bipolar disorder [7].
• BACKGROUND: Compelling evidence indicates that kappa opioid receptor (KOR) agonists produce perceptual distortions in animals and humans, yet the mechanism of action and clinical relevance of such effects remain unclear [8].

High impact information on OPRK1

• This study provided evidence for mRNA transport and regulation of presynaptic protein synthesis of nonstructural proteins like KOR in primary sensory neurons and demonstrated a mechanism of KCl depolarization-stimulated axonal mRNA redistribution for localized translational regulation [9].
• Using reverse transcriptase-polymerase chain reaction and sequencing analyses, we found that mRNA for the KOR was constitutively expressed in microglia and determined that the nucleotide sequence of the open reading frame was identical to that of the human brain KOR gene [1].
• Significantly, and in agreement with our in silico predictions, substituted cysteine accessibility method analysis of helix 2 comparing KOR and the delta-opioid receptor, which has negligible affinity for salvinorin A, revealed that residues known to be important for salvinorin A binding exhibit a differential pattern of water accessibility [10].
• When expressed in Chinese hamster ovary (CHO) cells, GEC1 co-immunoprecipitated with FLAG-hKOR [11].
• TNFalpha and IL-1beta both suppressed the expression of DOR and KOR mRNA in both OA and RA FLS [12].

Chemical compound and disease context of OPRK1

• Results of flow cytometry studies suggested that the mechanism whereby KOR ligands inhibit cocaine's stimulatory effect on viral expression involves the suppression of cocaine-induced activation of extracellular signal-regulated kinase1/2, thereby blunting cocaine-enhanced up-regulation of the HIV-1 entry chemokine coreceptor CCR5 [13].
• The kappa opioid receptor (KOR) agonist U50,488 recently has been shown to inhibit HIV-1 p24 antigen production in acutely infected microglial cell cultures [14].

Biological context of OPRK1

• Family-based analyses demonstrated associations between alcohol dependence and multiple SNPs in the promoter and 3' end of PDYN, and in intron 2 of OPRK1 [15].
• To define the effects of phosphorylation of this residue in desensitization and internalization processes in mammalian expression systems, wild-type KOR-green fluorescent protein (KOR-GFP) and KOR(S369A)-GFP were stably expressed in AtT-20 and HEK293 cells [16].
• Direct sequencing of amplified DNA containing all four exons and intron 1 of the hOPRK1 gene were evaluated for polymorphisms in 291 subjects (145 former heroin addicts and 146 controls) [5].
• Most interestingly, the KOR agonist U69593 may exert an antiarthritic effect via up-regulation of KOR in OA and RA FLS [12].
• Following 4-h incubation, all three compounds induced down-regulation of the human KOR, with salvinorin A causing a lower extent of down-regulation [17].

Anatomical context of OPRK1

• These findings suggest that the dysfunction of MOR, but not DOR and KOR, linked to cPKC activation in the spinal cord may be, at least in part, involved in the reduced sensitivity to antinociception induced by morphine under the ethanol-dependent neuropathic pain-like state [18].
• In the present study, the relative distribution of each type of opioid receptor, mu (MOR), delta (DOR) and kappa (KOR) within GABAergic neurons in the inferior colliculus was examined [19].
• Using heterologous expression in Xenopus laevis oocytes, we compared the potencies of morphine, morphine-6beta-glucuronide (M6G), and morphine-3-glucuronide (M3G) for cloned human mu- (hMOR), kappa- (hKOR), and delta-opioid receptors (hDOR) [20].
• Using immunofluorescence, both DOR and KOR proteins were expressed predominantly on the cell membrane with minor staining in the cytoplasm [21].
• Skin fibroblasts in culture expressed DOR and KOR mRNA [21].

Associations of OPRK1 with chemical compounds

• Opioid Receptor Gene (OPRM1, OPRK1, and OPRD1) Variants and Response to Naltrexone Treatment for Alcohol Dependence: Results From the VA Cooperative Study [22].
• These results demonstrate that GRK-mediated phosphorylation of serine 369 mediates rat KOR desensitization and internalization [16].
• The kappa opioid receptor (KOR) plays a role in stress responsivity, opiate withdrawal and responses to cocaine [5].
• In contrast, the prototypical nitrogenous KOR agonist U69593 and the endogenous peptidergic agonist dynorphin A (1-13) showed differential requirements for these three residues for binding and activation [23].
• KOR activation by its endogenous ligand dynorphin A(1-17) decreases basal and drug-induced striatal levels of dopamine [5].

Physical interactions of OPRK1

• Thus, NHERF-1/EBP50 binds directly to KOR, and this association plays an important role in accelerating Na(+)/H(+) exchange [24].

Regulatory relationships of OPRK1

• The kappa-agonist U50,488H induced a modest inositol phosphate formation when KOR was expressed alone or with MOR, but the response was attenuated when co-expressing with either DOR or ORL(1) [25].

Other interactions of OPRK1

• To investigate the possibility that dynorphin A may serve as an agonist for other opioid receptors, we took the advantage of the cloning of the three major types of opioid receptors, mu (MOR), delta (DOR) and KOR, and examined their affinity for and their activation by dynorphin A [26].
• Expression of GEC1 greatly increased total and cell-surface KOR but not mu or delta opioid receptors [11].
• The trans-(3,4)-dimethyl-4-(3-hydroxyphenyl)piperidines are a unique class of opioid antagonists that have recently provided selective antagonists for mu-opioid receptors (MOR) and kappa-opioid receptors (KOR) [27].

Analytical, diagnostic and therapeutic context of OPRK1

• The expression of KOR in microglial cells was confirmed by membrane binding of [3H]U69,593, a kappa-selective ligand, and by indirect immunofluorescence [1].
• Using immunohistochemistry, DOR and KOR were localized in skin fibroblast-like and mononuclear cells [21].
• Interestingly, the modified MOR is expressed at six times higher levels than wild-type MOR and is similarly stable as wild-type KOR after immobilization [28].
• To investigate the contribution of the kappa-opioid receptor (KOR) to opioid function in vivo, we have generated KOR-deficient mice by gene targeting [29].
• MATERIALS AND METHODS: Dynorphin A, N-methyl-D: -aspartate (NMDA) and kappa opioid receptor (KOR) were measured in spinal cord, dorsal root ganglia, peripheral nerves and foot skin of control and streptozotocin-induced diabetic rats by immunoassay and Western blotting [4].

References