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

Accepted version
Peer-reviewed

Repository DOI


Type

Article

Change log

Authors

Nestor, Liam J 
Subramaniam, Naresh 
Dodds, Chris 
Nathan, Pradeep J 

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.

Description

Keywords

Adolescent, Adult, Aged, Alanine, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Drinking, Eating, Female, Glycine, Humans, Indans, Male, Middle Aged, Naltrexone, Narcotic Antagonists, Pharmacogenomic Testing, Polymorphism, Single Nucleotide, Receptors, Opioid, mu, Triazoles, Young Adult

Journal Title

Neuropsychopharmacology

Conference Name

Journal ISSN

0893-133X
1740-634X

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_PC_12012)
This study was sponsored and funded by GlaxoSmithKline (GSK), which has a commercial interest in GSK1521498. HZ and NS have received consultancy fees from GSK. ETB is employed half-time by the University of Cambridge and half-time by GSK; he holds stock in GSK. PJN, BKS, CD, LW and LN were former employees of GSK. SRM, LKH, BW, DW, LSVJ, DF, KM, AK and DBR are employees of GSK and hold stock in GSK.