Cortisol Stress Response in Men and Women Modulated Differentially by the Mu-Opioid Receptor Gene Polymorphism OPRM1 A118G

Neuropsychopharmacology. 2015 Oct;40(11):2546-54. doi: 10.1038/npp.2015.101. Epub 2015 Apr 16.


Differences in stress reactivity may affect long-term health outcomes, but there is little information on how these differences arise. The stress axis is regulated by, in part, the endogenous opioid, beta-endorphin, acting on mu-opioid receptors. Persons carrying one or two copies of the G allele of the mu-opioid receptor gene (OPRM1 A118G) may have higher receptor binding for beta-endorphin compared with AA homozygotes that may contribute to individual differences in cortisol reactivity to stress, leading to a relative blunting of cortisol stress reactivity in G allele genotypes. We measured cortisol in 251 young adults (69 GA/GG vs 182 AA genotypes) exposed to mental arithmetic plus public speaking stress relative to a resting control day. Women had smaller cortisol responses than men (F=10.2, p=0.002), and women with GA or GG genotypes (N=39) had an absence of cortisol response relative to AA carriers (N=110) (F=18.4, p<0.0001). Male genotypes had no such difference in response (F=0.29). Cortisol response following mu-opioid receptor blockade using naltrexone in 119 of these subjects unmasked a greater tonic opioid inhibition of cortisol secretion in women (N=64), consistent with their blunted stress reactivity. Compared with men, women may have cortisol stress responses that are more heavily regulated by endogenous opioid mechanisms, and the OPRM1 GA/GG genotypes may affect females differentially relative to males. Diminished cortisol responses to stress may have consequences for health behaviors in women with GA/GG genotypes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Double-Blind Method
  • Female
  • Genotype
  • Heart Rate / drug effects
  • Heart Rate / physiology
  • Humans
  • Hydrocortisone / metabolism*
  • Male
  • Mathematical Concepts
  • Naltrexone / administration & dosage
  • Narcotic Antagonists / administration & dosage
  • Polymorphism, Single Nucleotide*
  • Random Allocation
  • Receptors, Opioid, mu / genetics*
  • Saliva / drug effects
  • Saliva / metabolism
  • Sex Characteristics
  • Social Perception
  • Stress, Psychological / drug therapy
  • Stress, Psychological / genetics*
  • Stress, Psychological / physiopathology*
  • Young Adult


  • Narcotic Antagonists
  • OPRM1 protein, human
  • Receptors, Opioid, mu
  • Naltrexone
  • Hydrocortisone