Mu‐opioid receptor A118G polymorphism in healthy volunteers affects hypothalamic–pituitary–adrenal axis adrenocorticotropic hormone stress response to metyrapone

Abstract

The mu-opioid receptor encoded by the gene OPRM1 plays a primary role in opiate, alcohol, cocaine and nicotine addiction. Studies using opioid antagonists demonstrate that the mu-opioid receptor (MOP-r) also mediates the hypothalamic–pituitary–adrenal (HPA) axis stress response. A common polymorphism in exon one of the MOP-r gene, A118G, has been shown to significantly alter receptor function and MOP-r gene expression; therefore, this variant likely affects HPA-axis responsivity. In the current study, we have investigated whether the presence of the 118AG variant genotype affects HPA axis responsivity to the stressor metyrapone, which transiently blocks glucocorticoid production in the adrenal cortex. Forty-eight normal and healthy volunteers (32 men, 16 women) were studied, among whom nine men and seven women had the 118AG genotype. The 118G allele blunted the adrenocorticotropic hormone (ACTH) response to metyrapone. Although there was no difference in basal levels of ACTH, subjects with the 118AG genotype had a more modest rise and resultant significantly lower ACTH levels than those with the prototype 118AA at the 8-hour time point (P < 0.02). We found no significant difference between genders. These findings suggest a relatively greater tonic inhibition at hypothalamic–pituitary sites through the mu-opioid receptor and relatively less cyclical glucocorticoid inhibition in subjects with the 118G allele.

Pharmacogenetics of Naltrexone in Asian Americans: A Randomized Placebo-Controlled Laboratory Study

“…Previous studies of HPA-axis challenges with naloxone (Hernandez-Avila et al, 2003Wand et al, 2002), and more recently with metyrapone (Ducat et al, 2011), have suggested an intriguing pharmacogenetic effect. Consistent with our previous study (Ray et al, 2009a), results revealed a significant main effect of alcohol, such that it decreased both cortisol and ACTH relative to baseline.…”

Alcohol: A stimulant activating brain stress responsive systems with persistent neuroadaptation

“…In two studies from this laboratory, the 118G variant was associated with alcoholism and heroin addiction in a sample of Swedish subjects with little genetic admixture (Bart et al, 2004. Of interest, the 118G allele has been associated with various phenotypes including attenuated HPA axis response to stress, and reduced clinical effects of opioid analgesics, although the findings were not always consistent (e.g., Oertel et al, 2009): positive effect of the 118G allele on treatment response to the opioid antagonist, naltrexone (Sturgess et al, 2011); an association with a robust cortisol response to the mu opioid receptor competitive antagonist naloxone, in a population-specific manner (Wand et al, 2002;Chong et al, 2006); and a blunted ACTH response to metyrapone in healthy subjects (Ducat et al, 2013).…”

The genetics of the opioid system and specific drug addictions

“…The 118G allele blunted the ACTH response to metyrapone in healthy subjects (Ducat et al 2011). 118G carriers in buprenorphine maintenance treatment showed even greater attenuated response to metyrapone compared to 118A carriers, indicating more potent HPA axis suppression by buprenorphine in 118G carriers (Kakko et al 2008).…”