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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 iv 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 …