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Blunted Opiate Modulation of Hypothalamic-Pituitary-Adrenocortical Activity in Men and Women Who Smoke

From the Departments of Behavioral Sciences (M.A.), Family Medicine (M.A., R.W.), Physiology/Pharmacology (M.A., L.E.W.), and Psychiatry (D.H.), University of Minnesota Medical School, Duluth, Minnesota.

Address correspondence and reprint requests to Mustafa al'Absi, Department of Behavioral Sciences, University of Minnesota Medical School, Duluth, MN 55812. E-mail: malabsi{at}umn.edu

Objective: To examine the extent to which nicotine dependence alters endogenous opioid regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis functions. Endogenous opiates play an important role in regulating mood, pain, and drug reward. They also regulate the HPA functions. Previous work has demonstrated an abnormal HPA response to psychological stress among dependent smokers.

Methods: Smokers and nonsmokers (total n = 48 participants) completed two sessions during which a placebo or 50 mg of naltrexone was administered, using a double-blind design. Blood and saliva samples, cardiovascular and mood measures were obtained during a resting absorption period, after exposure to two noxious stimuli, and during an extended recovery period. Thermal pain threshold and tolerance were assessed in both sessions. Participants also rated pain during a 90-second cold pressor test.

Results: Opioid blockade increased adrenocorticotropin, plasma cortisol, and salivary cortisol levels; these increases were enhanced by exposure to the noxious stimuli. These responses were blunted in smokers relative to nonsmokers. Smokers tended to report less pain than nonsmokers, and women reported more pain during both pain procedures, although sex differences in pain were significant only among nonsmokers.

Conclusions: We conclude that nicotine dependence is associated with attenuated opioid modulation of the HPA. This dysregulation may play a role in the previously observed blunted responses to stress among dependent smokers.

Key Words: smoking • endogenous opioids • cortisol • adrenocorticotropin • stress • pain • naltrexone

Abbreviations: ACTH = adrenocorticotropin; BP = blood pressure; CO = cardiac output; CPT = cold pressor test; CRF = corticotrophin-releasing factor; HPA = hypothalamic-pituitary-adrenocortical; MPQ = McGill Pain Questionnaire.