Opioid Antagonists and the A118G Polymorphism in the μ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype

Abstract

The A118G single-nucleotide polymorphism (SNP rs1799971) in the μ-opioid receptor gene, OPRM1, has been much studied in relation to alcohol use disorders. The reported effects of allelic variation at this SNP on alcohol-related behaviors, and on opioid receptor antagonist treatments, have been inconsistent. We investigated the pharmacogenetic interaction between A118G variation and the effects of two μ-opioid receptor antagonists in a clinical lab setting. Fifty-six overweight and moderate–heavy drinkers were prospectively stratified by genotype (29 AA homozygotes, 27 carriers of at least 1 G allele) in a double-blind placebo-controlled, three-period crossover design with naltrexone (NTX; 25 mg OD for 2 days, then 50 mg OD for 3 days) and GSK1521498 (10 mg OD for 5 days). The primary end point was regional brain activation by the contrast between alcohol and neutral tastes measured using functional magnetic resonance imaging (fMRI). Secondary end points included other fMRI contrasts, subjective responses to intravenous alcohol challenge, and food intake. GSK1521498 (but not NTX) significantly attenuated fMRI activation by appetitive tastes in the midbrain and amygdala. GSK1521498 (and NTX to a lesser extent) significantly affected self-reported responses to alcohol infusion. Both drugs reduced food intake. Across all end points, there was less robust evidence for significant effects of OPRM1 allelic variation, or for pharmacogenetic interactions between genotype and drug treatment. These results do not support strong modulatory effects of OPRM1 genetic variation on opioid receptor antagonist attenuation of alcohol- and food-related behaviors. However, they do support further investigation of GSK1521498 as a potential therapeutic for alcohol use and eating disorders.

Predictors of Naltrexone Response in a Randomized Trial: Reward-Related Brain Activation, OPRM1 Genotype, and Smoking Status

“…Several factors could explain the null pharmacogenetic effect. First, this result is consistent with the absence of a pharmacogenetic interaction on drinking during the medication period, as well as with four previous studies (Mann et al, 2014;Schacht et al, 2013c;Weerts et al, 2013;Ziauddeen et al, 2016), including PREDICT, where A118G genotype did not moderate relationships between baseline activation and the effects of NTX on drinking. Second, although previous studies have reported greater cue-elicited activation among G-allele carriers, these studies have primarily enrolled small numbers of non-treatment seekers with relatively low levels of drinking.…”

“…Independent of NTX, the A118G G-allele has been associated with greater alcohol cue-elicited activation (Bach et al, 2015;Filbey et al, 2008;Ray et al, 2014) and enhanced striatal dopamine response to intravenous ethanol (Ramchandani et al, 2011), suggesting that OPRM1 genotype might moderate the effects of NTX on this phenotype; however, G-allele carrier sample sizes have been small. Prospectively genotyped studies with more G-allele carriers have reported little evidence of an interaction between A118G genotype and NTX (50 mg, 5-7 days) on cue-elicited midbrain, VS, mPFC, ACC, OFC, insula, or amygdala activation (Schacht et al, 2013c;Ziauddeen et al, 2016), or on global binding of the selective μ-opioid agonist [11(C)]-carfentanil (Weerts et al, 2013). However, overall, neuroimaging studies of NTX and OPRM1 genotype have primarily enrolled non-treatment seekers and have largely failed to include baseline scans, leaving open the possibility that reported differences between medication and/or OPRM1 groups are pre-existing or do not extend to treatment-seeking subjects, whose AUDs are more severe (Rohn et al, 2017).…”

Evidence for a Long-Lasting Compulsive Alcohol Seeking Phenotype in Rats

“…The accumulated data suggest that GSK1521498 may be a more generally effective μ-opioid antagonist treatment across a broad spectrum of individuals addicted to alcohol, since it has the effect to decrease not only compulsive seeking behavior, but also the impact of alcohol cues and alcohol drinking that lead to relapse in otherwise abstinent individuals. Moreover, our findings are consonant with experimental medicine studies that have shown GSK1521498 to be well tolerated in humans and able to reduce self-reported responses to alcohol (Ziauddeen et al, 2016), indicating its significant translational potential as a potential treatment for alcoholism. Appropriately designed clinical trials of this putative treatment would be both indicated and timely.…”

“…Opioid receptor-mediated mechanisms have been shown to reduce alcohol drinking, craving for alcohol and established CS-controlled alcohol seeking (Vengeliene et al, 2008); moreover μ-opioid receptors in the prefrontal context have been implicated in compulsive eating (Blasio et al, 2014). We have therefore investigated μ-opioid mechanisms in compulsive alcohol seeking in our newly established procedure using the most selective and well-characterized, in vitro and in vivo (Giuliano et al, 2012(Giuliano et al, , 2013Ignar et al, 2011;Kelly et al, 2015;Ripley et al, 2015;Ziauddeen et al, 2013Ziauddeen et al, , 2016, μ-opioid receptor antagonist GSK1521498. We have shown previously that this compound is more effective than naltrexone in reducing cue-controlled alcohol seeking and also alcohol drinking .…”

Lack of associations of the opioid receptor mu 1 (OPRM1) A118G polymorphism (rs1799971) with alcohol dependence: review and meta-analysis of retrospective controlled studies

“…[ 32 , 33 ] Therefore, we focused our study on OPRM1 A118G, which is a functional allelic-variant with deleterious effects on protein and mRNA expressions. [ 34 ]…”