The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine.
Large individual differences in the clinical response to morphine therapy have been known for a long time by clinicians. The recent advances in genomic research encourage the search for pharmacogenetic causes of that variability. As a measure of central opioid effects, pupil diameters were assessed every 20 min for 18 h after administration of morphine or its active metabolite morphine-6-glucuronide (M6G) in a two-way crossover study. The opioid effects were compared between six subjects with a single-nucleotide polymorphism (SNP) A118G in the mu-opioid receptor gene (five heterozygous, one homozygous) and six control subjects. Non-parametric pharmacokinetic-pharmacodynamic modelling was employed to identify the influence of the A118G SNP on the concentration-response relationship of M6G and morphine, which was described by a sigmoid Emax model. As a measure of potency, the EC50 of the pupil constrictory effects of M6G was 714 +/- 197 nmol/l in wild-type and 1475 +/- 424 nmol/l in heterozygous carriers of the A118G SNP. In the homozygous carrier of the SNP, it had an EC50 of 3140 nmol/l. In addition, the dose-response relationship was flatter in the A118G carriers than in control subjects (shape factor of the sigmoid Emax model: gamma = 3.3 +/- 1.2, 1.7 +/- 0.5 and 1.6 for wild-type, heterozygous and the homozygous A118G carriers, respectively). In contrast, the concentration-response relationship of morphine was not affected by this specific SNP. The A118G SNP in the mu-receptor gene significantly reduces the potency of M6G in humans.
Lötsch
Jörn
J
Pharmazentrum Frankfurt, Johann Wolfgang Goethe-University, Frankfurt, Germany. j.loetsch@em.uni-frankfurt.de
Skarke
Carsten
C
Grösch
Sabine
S
Darimont
Jutta
J
Schmidt
Helmut
H
Geisslinger
Gerd
G
D000328:Adult; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D008297:Male; D009022:Morphine Derivatives / Q000097:blood / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011680:Pupil / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000235:genetics*
D009022:Morphine Derivatives; D017450:Receptors, Opioid, mu; C035349:morphine-6-glucuronide