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Polymorphisms of the kappa opioid receptor and prodynorphin genes: HIV risk and HIV natural history.

ABSTRACT: OBJECTIVE:Studies indicate cross-desensitization between opioid receptors (eg, kappa opioid receptor, OPRK1) and chemokine receptors (eg, CXCR4) involved in HIV infection. Whether gene variants of OPRK1 and its ligand, prodynorphin (PDYN), influence the outcome of HIV therapy was tested. METHODS:Three study points, admission to the Women's Interagency HIV Study, initiation of highly active antiretroviral therapy (HAART), and the most recent visit, were chosen for analysis as crucial events in the clinical history of the HIV patients. Regression analyses of 17 variants of OPRK1 and 11 variants of PDYN with change of viral load (VL) and CD4 count between admission and initiation of HAART and initiation of HAART to the most recent visit to Women's Interagency HIV Study were performed in 598 HIV+ subjects, including African Americans, Hispanics, and Whites. Association with HIV status was done in 1009 subjects. RESULTS:Before HAART, greater VL decline (improvement) in carriers of PDYN IVS3+189C>T and greater increase of CD4 count (improvement) in carriers of OPRK -72C>T were found in African Americans. Also, greater increase of CD4 count in carriers of OPRK1 IVS2+7886A>G and greater decline of CD4 count (deterioration) in carriers of OPRK1 -1205G>A were found in Whites. After HAART, greater decline of VL in carriers of OPRK1 IVS2+2225G>A and greater increase of VL in carriers of OPRK1 IVS2+10658G>T and IVS2+10963A>G were found in Whites. Also, a lesser increase of CD4 count was found in Hispanic carriers of OPRK1 IVS2+2225G>A. CONCLUSIONS:OPRK1 and PDYN polymorphisms may alter severity of HIV infection and response to treatment.

SUBMITTER: Proudnikov D

PROVIDER: S-EPMC3625517 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Polymorphisms of the kappa opioid receptor and prodynorphin genes: HIV risk and HIV natural history.

Proudnikov Dmitri D Randesi Matthew M Levran Orna O Yuferov Vadim V Crystal Howard H Ho Ann A Ott Jurg J Kreek Mary J MJ

Journal of acquired immune deficiency syndromes (1999) 20130501 1

<h4>Objective</h4>Studies indicate cross-desensitization between opioid receptors (eg, kappa opioid receptor, OPRK1) and chemokine receptors (eg, CXCR4) involved in HIV infection. Whether gene variants of OPRK1 and its ligand, prodynorphin (PDYN), influence the outcome of HIV therapy was tested.<h4>Methods</h4>Three study points, admission to the Women's Interagency HIV Study, initiation of highly active antiretroviral therapy (HAART), and the most recent visit, were chosen for analysis as cruci ...[more]

PMID: 23392455

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Project description:BackgroundThe misuse of opioids stems, in part, from inadequate knowledge of molecular interactions between opioids and opioid receptors. It is still unclear why some opioids are far more addictive than others. The κ-opioid receptor (KOR) plays a critical role in modulating pain, addiction, and many other physiological and pathological processes. Butorphanol, an opioid analgesic, is a less addictive opioid with unique pharmacological profiles. In this study, we investigated the interaction between butorphanol and KOR to obtain insights into the safe usage of this medication.MethodsWe determined the binding affinity of butorphanol to KOR with a naltrexone competition study. Recombinant KORs expressed in mammalian cell membranes (Chem-1) were used for G-protein activation studies, and a human embryonic kidney-293 (HEK-293) cell line stably transfected with the human KOR was used for β-arrestin study as previously described in the literature. The effects of butorphanol on KOR internalization were investigated using mouse neuroblastoma Neuro2A cells stably transfected with mKOR-tdTomato fusion protein (N2A-mKOR-tdT) cells overexpressing KOR. The active-state KOR crystal structure was used for docking calculation of butorphanol to characterize the ligand binding site. Salvinorin A, a full KOR agonist, was used as a control for comparison.ResultsThe affinity of KOR for butorphanol is characterized by Kd of 0.1 ± 0.02 nM, about 20-fold higher compared with that of the µ-opioid receptor (MOR; 2.4 ± 1.2 nM). Our data indicate that butorphanol is more potent on KOR than on MOR. In addition, butorphanol acts as a partial agonist of KOR in the G-protein activation pathway and is a full agonist on the β-arrestin recruitment pathway, similar to that of salvinorin A. The activation of the β-arrestin pathway is further confirmed by KOR internalization. The in silico docking model indicates that both salvinorin A and butorphanol share the same binding cavity with the KOR full agonist MP1104. This cavity plays an important role in determining either agonist or antagonist effects of the ligand.ConclusionsIn conclusion, butorphanol is a partial KOR agonist in the G-protein activation pathway and a potent KOR full agonist in the β-arrestin recruitment pathway. The structure analysis offers insights into the molecular mechanism of KOR interaction and activation by butorphanol.

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Polymorphisms of the kappa opioid receptor and prodynorphin genes: HIV risk and HIV natural history.

Publications

Polymorphisms of the kappa opioid receptor and prodynorphin genes: HIV risk and HIV natural history.

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