Acute HPA axis response to naltrexone differs in female vs. male smokers.
BACKGROUND
Both opioid antagonist administration and cigarette smoking acutely increase hypothalamic-pituitary-adrenal (HPA) axis activity as measured by adrenocorticotropic hormone (ACTH) and cortisol levels. However, male and female smokers may differ in their response to the opioid antagonist naltrexone, which may be partially mediated by sex differences in HPA axis function. Smokers, as a group, have frequently been shown to have HPA axis dysfunction, which may have relevance to the course and maintenance of nicotine dependence. The purpose of this study was to examine possible sex differences in HPA axis function by comparing stress-hormone response to naltrexone within healthy male and female smokers. Additionally, exploratory analyses compared the combined effects of naltrexone and cigarette smoking on hormonal responsivity between the sexes.


METHODS
Thirty-eight healthy smokers (22 men) were tested in two separate morning sessions after 12h of smoking abstinence. For women, self-reports of menstrual cycle information were obtained prior to each session (date of last menstruation, cycle length, reproductive phase, etc.). Each participant received 50mg naltrexone or placebo capsule (in random order) and plasma levels of ACTH and cortisol were assessed at regular intervals for several hours. A subgroup of 12 participants underwent a similar, additional session in which they smoked a single cigarette three hours after naltrexone administration.


RESULTS
Naltrexone significantly increased ACTH and cortisol levels in women, but not men (DrugxSexxTime, p<0.05). A post hoc analysis suggested that women at an estimated 'high estrogen' phase had a greater cortisol response (DrugxEstrogen level, p<0.05) than those at an estimated 'low estrogen' phase. Exploratory analyses showed that smoking a single cigarette potentiated naltrexone-induced increases in ACTH (p<0.05) and cortisol (p<0.01) in all participants.


CONCLUSIONS
The findings support the hypothesis that women are more sensitive to opioid antagonism at the level of the HPA axis. Although further studies are needed to examine mechanisms underlying these responses, both results may have clinical implications for the use of naltrexone as a treatment for nicotine dependence.
Roche
Daniel J O
DJ
Committee on Neurobiology, University of Chicago, 947 E. 58th St., Chicago, IL 60637, United States. jabelson@umich.edu
Childs
Emma
E
Epstein
Alyssa M
AM
King
Andrea C
AC
D000324:Adrenocorticotropic Hormone / Q000032:analysis / Q000097:blood / Q000378:metabolism; D000328:Adult; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis / Q000097:blood / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D010919:Placebos; D012727:Sex Characteristics; D012907:Smoking / Q000097:blood / Q000378:metabolism*; D013997:Time Factors; D055815:Young Adult
D009292:Narcotic Antagonists; D010919:Placebos; D009271:Naltrexone; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone