Differential responsivity of the hypothalamic-pituitary-adrenal axis to glucocorticoid negative-feedback and corticotropin releasing hormone in rats undergoing morphine withdrawal: Possible mechanisms involved in facilitatedand attenuated stress responses

Chronic morphine treatment produces profound and long-lasting changes in th e pituitary-adrenal responses to stressful stimuli. The purpose of the pres ent study was to explore the mechanisms involved in these altered stress re sponses. Chronic morphine administration increased basal plasma concentrati ons of corticosterone and adrenocorticotropic hormone (ACTH), which peaked at 36 h after the final morphine injection and returned to normal levels wi thin 84-h. Whole brain glucocorticoid receptor protein expression was reduc ed (approximately 70%) in morphine-treated rats 4-h after the final morphin e injection and these levels recovered within 16-h. Twelve hours following morphine withdrawal, rats displayed normal ACTH, but potentiated and prolon ged corticosterone responses to restraint stress. Both the ACTH and cortico sterone responses to restraint in acutely withdrawn rats were insensitive t o dexamethasone. Furthermore, acutely withdrawn rats displayed reduced ACTH but prolonged corticosterone responses to peripheral corticotropin-releasi ng hormone (CRH) administration. These findings suggest that the normal ACT H and enhanced corticosterone responses to stress in acutely withdrawn rats involved decreased sensitivity of negative-feedback systems to glucocortic oids, reduced pituitary responsivity to CRH, and enhanced sensitivity of th e adrenals to ACTH. Eight days following morphine withdrawal, rats displaye d dramatically reduced ACTH, but normal corticosterone responses to restrai nt stress. These rats displayed enhanced sensitivity to dexamethasone and n ormal pituitary-adrenal responses to CRH. These data suggest that the reduc ed ACTH responses to stress in 8-day withdrawal rats involved increased sen sitivity of negative-feedback systems to glucocorticoids as well as reduced CRH and/or AVP function in response to stress. Taken together, the results of this study illustrate some of the mechanisms mediating altered stress r esponsivity in rats that have received chronic morphine treatment.