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.

Figure 1

LD plot from Haploview 4.1 for EA subjects based on HapMap (phase II) data for individuals of European Ancestry for the (A) OPRD1 and (B) OPRK1 tSNPs examined in this study. Pair-wise SNP |D′| values (×100) of linkage are shown along with 2 haplotype blocks identified using the four-gamete rule. Darkened blocks indicate SNP pairs without evidence of extensive recombination (i.e., 4-gamete rule for haplotype block characterization with at least one 2-SNP haplotype having a frequency < 0.02).

Figure 2

Effect of OPRK1^2 genotype on sedation while on naltrexone versus placebo. Data presented are predicted values based on betas from mixed-model regression analyses. TT homozygotes showed reduced sedation while on naltrexone.

Figure 3

Effect of OPRD10^4 genotype on alcohol-induced stimulation while on naltrexone versus placebo. Data presented are predicted values based on betas from mixed-model regression analyses. A-allele carriers showed naltrexone-induced blunting of alcohol stimulation. An asterisk (** p < 0.01) indicates a significant effect of medication within a genotype group across the infusion session

Figure 4

Effect of OPRD1^4 genotype on alcohol craving while on naltrexone versus placebo. Data presented are predicted values based on betas from mixed-model regression analyses. A-allele carriers showed naltrexone-induced attenuation of alcohol craving. An asterisk (* p < 0.05) indicates a significant effect of medication within a genotype group across the infusion session.