The mu-opioid receptor polymorphism A118G predicts cortisol responses to naloxone and stress.
A polymorphism in the mu-opioid receptor (MOR) (A118G) has been shown to increase beta-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.
Chong
Rachel Y
RY
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Oswald
Lynn
L
Yang
Xiaoju
X
Uhart
Magdalena
M
Lin
Ping-I
PI
Wand
Gary S
GS
D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000483:Alleles; D004247:DNA / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D008297:Male; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000523:psychology; D012931:Social Environment; D013315:Stress, Psychological / Q000097:blood*
D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009270:Naloxone; D000324:Adrenocorticotropic Hormone; D004247:DNA; D006854:Hydrocortisone