The mu-opioid receptor polymorphism A118G predicts cortisol responses to naloxone and stress

Rachel Y. Chong, Lynn Oswald, Xiaoju Yang, Magdalena Uhart, Ping I. Lin, Gary S. Wand

Research output: Contribution to journalArticlepeer-review

130 Scopus citations


A polymorphism in the mu-opioid receptor (MOR) (A118G) has been shown to increase β-endorphin binding affinity, theoretically placing greater inhibitory tone on hypothalamic corticotropin-releasing hormone (CRH) neurons. We hypothesized that the minor allele (G) would predict cortisol responses to both pharmacological (naloxone) and psychological (stress) activation of the hypothalamic-pituitary-adrenal (HPA) axis. Healthy subjects (mean age 25.2 years, SD 9.2 years) completed a naloxone challenge (n = 74) and/or the modified Trier Social Stress Test (TSST) (n = 86). For the naloxone challenge, two baseline blood samples were obtained. Then, five increasing doses of i.v. naloxone were administered at 30-min intervals and 12 additional blood samples were collected at 15-min intervals. The TSST consisted of 5-min of public speaking and 5-min of mental arithmetic exercises. Three baseline and five post-TSST blood samples were drawn. Both the naloxone and TSST groups had significant adrenocorticotropin (ACTH) and cortisol responses to their respective challenges (P < 0.001). There were no differences in baseline ACTH, baseline cortisol, or ACTH response by genotype in either the naloxone or the TSST group. Among subjects expressing a G allele, there was a higher cortisol response to naloxone (P = 0.046), but a lower cortisol response to the TSST (P = 0.044). In conclusion, the minor allele (G) was associated with a robust cortisol response to naloxone blockade, but a blunted response to psychosocial stress. We speculate that increased opioid avidity of the minor allele receptor contributes to the differential response to naloxone vs stress.

Original languageEnglish (US)
Pages (from-to)204-211
Number of pages8
Issue number1
StatePublished - Jan 2006


  • Adrenocorticotropin
  • Cortisol
  • Naloxone
  • Opioid receptor
  • Polymorphism
  • Stress

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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