Intermittent Morphine Administration Induces Dependence and is a Chronic Stressor in Rats

Although constant treatment with morphine (implanted pellets) does not activate the hypothalamic–pituitary–adrenal (HPA) axis, intermittent injections of morphine may constitute a chronic stressor in rats. To test this hypothesis, we compared the effects of morphine in escalating doses (10–40 mg/kg, s.c.) or saline injected twice daily for 4 days on energy balance, hormones, HPA responses to novel restraint and central corticotropin-releasing factor (CRF) mRNA 12 h and 8 days after the last morphine injection in adult male Sprague–Dawley rats. Weight gain stopped at the onset of morphine, weight loss was marked 36 h postmorphine; thereafter, body weight gain paralleled saline controls. At 12 h, insulin, leptin, and testosterone concentrations were reduced but normalized by 8 days. Restraint and tail nicks caused facilitated ACTH responses at 12 h, under-responsiveness at 8 days. CRF mRNA, measured only at 12 h, was increased in the paraventricular (PVN) and Barrington's nuclei (BAR), decreased in the bed nuclei of the stria terminalis (BNST) and unchanged in the amygdala (CeA) in morphine-treated rats. After stress, CRF mRNA increased in PVN in both groups, increased in BAR and decreased in BNST in saline but not morphine groups, and was unchanged in CeA in both groups. Results from all variables characterize intermittent morphine injections as a chronic stressor. In contrast to constant treatment, injected morphine probably allows some withdrawal during each 12 h interval, causing repeated stress. Drug addicts treat themselves intermittently, and stress causes relapse after withdrawal. Thus, intermittent morphine, itself, may promote relapse.