Time-dependent alterations in mRNA expression of brain neuropeptides regulating energy balance and hypothalamo-pituitary-adrenal activity after withdrawal from intermittent morphine treatment

Chronic stressors alter brain function and may leave traces after their relief. We used intermittent morphine treatment to examine the relationships between stress-induced changes in energy balance and hypothalamo-pituitary-adrenal (HPA) activity and the recovery thereafter. We studied the effects of morphine injections on energy balance, hormones and fat stores, brain neuropeptide expression, and the ACTH and corticosterone responses to restraint 12 hr after the final injection and 8 d later during recovery. Weight gain, food intake, and caloric efficiency decreased at morphine onset, and these were maintained throughout the morphine injections. At 12 hr, fat stores, leptin, insulin, and testosterone concentrations were reduced. Subsequently, body weight gain and food intake increased and caloric efficiency was above control during the final days. By the eighth recovery day, fat stores and peripheral hormones were no longer depressed. At 12 hr, an over-response of CRF mRNA to restraint occurred in the hypothalamus, similar to the facilitated ACTH and corticosterone responses. On day 8, the hypothalamic CRF mRNA response to restraint was still facilitated, opposite to inhibited ACTH responses. Hypothalamic CRF mRNA correlated highly with mesenteric fat weight in morphine-treated rats. We conclude that there is a prolonged recovery from chronic stressors involving interrelated changes in energy balance and HPA activity. Nonetheless, 8 d after withdrawal from morphine, rats still display facilitated central stress responses, similar to the HPA symptoms described in posttraumatic stress disorder patients. Repeated partial withdrawal associated with intermittent morphine treatment, compounded by complete withdrawal associated with termination of the treatment, is likely required for these metabolic and HPA derangements.