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Delta and kappa opioid receptor polymorphisms influence the effects of naltrexone on subjective responses to alcohol.

ABSTRACT: Naltrexone, one of four FDA-approved pharmacotherapies for alcohol dependence, has shown moderate efficacy in clinical trials. Pharmacogenetic effects have been reported such that allelic variation at the gene encoding the mu-opioid receptor (OPRM1, rs1799971) predicts naltrexone-induced blunting of the positively reinforcing effects of alcohol. However, naltrexone also binds, albeit to a lesser degree, to kappa and delta opioid receptors in the brain. This alternate binding presents the possibility that single nucleotide polymorphisms (SNPs) in the kappa and delta opioid receptor (OPRK1 and OPRD1) genes may contribute to naltrexone pharmacogenetics. Therefore, the goal of this exploratory study was to re-examine data from a double-blind placebo controlled laboratory trial of naltrexone for pharmacogenetic effects at kappa and delta opioid receptor tag SNPs. Participants were 40 heavy drinkers (12 female) who underwent an intravenous alcohol challenge paradigm after receiving naltrexone (50mg) or placebo in randomized and crossover fashion. Dependent variables were self-reported alcohol-induced stimulation, sedation, and craving. Multilevel models revealed a significant Naltrexone×OPRK1 Genotype (rs997917) interaction predicting alcohol-induced sedation, such that TT homozygotes reported lower naltrexone-induced alcohol sedation as compared to carriers of the C allele. Moreover, there was a significant Naltrexone×OPRD1 Genotype (rs4654327) interaction predicting alcohol-induced stimulation and craving, such that carriers of the A allele at this locus reported greater naltrexone-induced blunting of alcohol stimulation and alcohol craving compared to GG homozygotes. These findings suggest that additional pharmacogenetic effects in the opioid receptor system may account for individual differences in response to naltrexone in the human laboratory.

SUBMITTER: Ashenhurst JR

PROVIDER: S-EPMC3683577 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Delta and kappa opioid receptor polymorphisms influence the effects of naltrexone on subjective responses to alcohol.

Ashenhurst James R JR Bujarski Spencer S Ray Lara A LA

Pharmacology, biochemistry, and behavior 20120827 2

Naltrexone, one of four FDA-approved pharmacotherapies for alcohol dependence, has shown moderate efficacy in clinical trials. Pharmacogenetic effects have been reported such that allelic variation at the gene encoding the mu-opioid receptor (OPRM1, rs1799971) predicts naltrexone-induced blunting of the positively reinforcing effects of alcohol. However, naltrexone also binds, albeit to a lesser degree, to kappa and delta opioid receptors in the brain. This alternate binding presents the possibi ...[more]

PMID: 22954510

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Project description:BACKGROUND:Nalfurafine is the first clinically approved kappa-opioid receptor (KOP-r) agonist as an antipruritus drug with few side effects in humans (e.g., sedation, depression, and dysphoria). No study, however, has been done using nalfurafine on alcohol drinking in rodents or humans. METHODS:We investigated whether nalfurafine alone or in combination with mu-opioid receptor (MOP-r) antagonist naltrexone changed excessive alcohol drinking in male and female C57BL/6J (B6) mice subjected to a chronic intermittent-access drinking paradigm (2-bottle choice, 24-hour access every other day) for 3 weeks. Neuronal proopiomelanocortin enhancer (nPE) knockout mice with brain-specific deficiency of beta-endorphin (endogenous ligand of MOP-r) were used as a genetic control for the naltrexone effects. RESULTS:Single administration of nalfurafine decreased alcohol intake and preference in both male and female B6 mice in a dose-dependent manner. Pretreatment with nor-BNI (a selective KOP-r antagonist) blocked the nalfurafine effect on alcohol drinking, indicating a KOP-r-mediated mechanism. Pharmacological effects of a 5-dosing nalfurafine regimen were further evaluated: The repeated nalfurafine administrations decreased alcohol consumption without showing any blunted effects, suggesting nalfurafine did not develop a tolerance after the multidosing regimen tested. Nalfurafine did not produce any sedation (spontaneous locomotor activity), anhedonia-like (sucrose preference test), anxiety-like (elevated plus maze test), or dysphoria-like (conditioned place aversion test) behaviors, suggesting that nalfurafine had few side effects. Investigating synergistic effects between low-dose naltrexone and nalfurafine, we found that single combinations of nalfurafine and naltrexone, at doses lower than individual effective dose, profoundly decreased excessive alcohol intake in both sexes. The effect of nalfurafine on decreasing alcohol consumption was confirmed in nPE-/- mice, suggesting independent mechanisms by which nalfurafine and naltrexone reduced alcohol drinking. CONCLUSION:The clinically utilized KOP-r agonist nalfurafine in combination with low-dose naltrexone has potential in alcoholism treatment.

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Delta and kappa opioid receptor polymorphisms influence the effects of naltrexone on subjective responses to alcohol.

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Delta and kappa opioid receptor polymorphisms influence the effects of naltrexone on subjective responses to alcohol.

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