Population-specific effects of the Asn40Asp polymorphism at the mu-opioid receptor gene (OPRM1) on HPA-axis activation

Pharmacogenet Genomics. 2007 Dec;17(12):1031-8. doi: 10.1097/FPC.0b013e3282f0b99c.


Background: Studies in European Americans (EAs) have shown that the hypothalamic-pituitary-adrenal (HPA)-axis activation by the opioid blockade is moderated by the single nucleotide polymorphism (SNP) A118G (Asn40Asp) at the mu-opioid receptor locus (OPRM1). We examined the effect of this, and of five intronic OPRM1 SNPs, on adrenocorticotropic hormone and cortisol concentrations, following the placebo-controlled administration of naloxone to healthy individuals who were of EA or Asian ancestry.

Methods: We used a balanced, within-participant design with two test sessions to examine the hormonal responses to intravenous naloxone (an opioid antagonist) (125 microg/kg) or placebo in 29 healthy participants (62% men, 59% of Asian ancestry). DNA isolated from whole blood was PCR amplified and genotyped using a fluorogenic 5 nuclease assay (TaqMan) method.

Results: Consistent with earlier reports, participants with one or two Asp40 alleles (n=16) had a significantly greater cortisol response to naloxone than Asn40 homozygotes, but the effect was limited to EAs. Asians with the Asp40 allele did not show a greater increase in cortisol response compared with Asn40 homozygotes. None of the intronic SNPs was associated with cortisol response either directly or via an interaction effect with Asn40Asp.

Conclusions: Effects of the Asn40Asp polymorphism at OPRM1 on HPA-axis activation seem to be population-specific. The association between the Asn40Asp and the HPA-axis response to naloxone cannot, therefore, be explained with reference only to the amino acid substitution encoded by that polymorphism. Further research to understand the basis for the observed association is warranted.

Publication types

  • Controlled Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Adult
  • Alleles
  • Amino Acid Substitution
  • Asian People / genetics
  • Double-Blind Method
  • Female
  • Genetics, Population
  • Genotype
  • Humans
  • Hydrocortisone / blood
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / physiology*
  • Male
  • Naloxone / pharmacology
  • Pharmacogenetics
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / physiology*
  • Polymorphism, Single Nucleotide*
  • Receptors, Opioid, mu / genetics*
  • Receptors, Opioid, mu / metabolism
  • White People / genetics


  • OPRM1 protein, human
  • Receptors, Opioid, mu
  • Naloxone
  • Adrenocorticotropic Hormone
  • Hydrocortisone