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

Abstract

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.

Figures

Figure 1

Cortisol secretion across stress and nonstress days in (a, b) men and (c, d) women with OPRM1 A118G GA/GG vs AA genotypes. Genotype had no effect on cortisol responses to mental stress in men. Female G allele carrier had no stress response at any time point. Women carrying the AA genotype had the expected cortisol response. −p>0.10, *p<0.002, **p<0.0001 by Student's t test following analysis of variance.

Figure 2

Cortisol responses to 50 mg naltrexone in men and women with OPRM1 A118G GA/GG vs AA genotypes. (a) Females in both genotype groups had a robust cortisol response to naltrexone, consistent with unmasking a mu-opioid receptor-associated inhibition of the hypothalamic–pituitary–adrenocortical (HPA) axis. (b) Males have minimal cortisol responses to naltrexone, indicating a lack of tonic opioid inhibition of the HPA.