Opioid Antagonists and the A118G Polymorphism in the μ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype.
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.
Department of Psychiatry, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.|Wellcome Trust MRC Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.|Cambridgeshire and Peterborough NHS Foundation Trust, Fulbourn Hospital, Cambridge, UK.
Hisham
0000-0003-4044-1719
H
Ziauddeen
Department of Psychiatry, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.|Centre for Neuropsychopharmacology, Imperial College, London, UK.
Liam J
LJ
Nestor
Department of Psychiatry, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.|Wellcome Trust MRC Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
Naresh
N
Subramaniam
Department of Psychology, University of Exeter, Exeter, UK.
Chris
C
Dodds
Department of Psychiatry, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.|Neuroscience Center of Excellence, inVentiv Health Clinical, Maidenhead, UK.|School of Psychological Sciences, Monash University, Melbourne, VIC, Australia.
Pradeep J
PJ
Nathan
GSK Medicines Research Centre, Stevenage, UK.
Sam R
SR
Miller
Medimmune, Granta Park, Cambridge, UK.
Bhopinder K
BK
Sarai
GSK Clinical Unit, Cambridge Biomedical Campus, Cambridge, UK.
Kay
K
Maltby
GSK Clinical Unit, Cambridge Biomedical Campus, Cambridge, UK.
Disala
D
Fernando
Acclarogen, St John's Innovation Centre, Cambridge, UK.
Liling
L
Warren
GSK Medicines Research Centre, Stevenage, UK.
Louise K
LK
Hosking
Genetics, Target Science, GlaxoSmithKline, King of Prussia, PA, USA.
Dawn
D
Waterworth
GSK, Global Clinical Safety & Pharmacovigilance, Stockley Park, UK.
Anna
A
Korzeniowska
GSK, Global Clinical Safety & Pharmacovigilance, Stockley Park, UK.
Beta
B
Win
Academic Discovery Performance Unit, GlaxoSmithKline R&D, Stevenage, UK.
Duncan B
DB
Richards
Clinical Pharmacology Modeling & Simulation, GSK, Research Triangle Park, NC, USA.
Lakshmi
L
Vasist Johnson
Department of Psychiatry, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.|Wellcome Trust MRC Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.|Cambridgeshire and Peterborough NHS Foundation Trust, Fulbourn Hospital, Cambridge, UK.
Paul C
PC
Fletcher
Department of Psychiatry, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.|Cambridgeshire and Peterborough NHS Foundation Trust, Fulbourn Hospital, Cambridge, UK.|Academic Discovery Performance Unit, GlaxoSmithKline R&D, Stevenage, UK.
Edward T
ET
Bullmore
D000293:Adolescent; D000328:Adult; D000368:Aged; D000409:Alanine / Q000235:genetics; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004326:Drinking / Q000187:drug effects* / Q000235:genetics*; D004435:Eating / Q000187:drug effects / Q000235:genetics; D005260:Female; D005998:Glycine / Q000235:genetics; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D000071185:Pharmacogenomic Testing; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics*; D014230:Triazoles / Q000494:pharmacology*; D055815:Young Adult
D007189:Indans; C568078:N-((3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl)methyl)-2,3-dihydro-1H-inden-2-amine; D009292:Narcotic Antagonists; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D014230:Triazoles; D009271:Naltrexone; D000409:Alanine; D005998:Glycine