Chronic morphine treatment and hypothalamic -pituitary -adrenal axis activity in rats.

Abstract

Epidemiological, clinical, and laboratory studies have suggested an interaction between stress and opioids. Herein, the effects of chronic morphine administration on hypothalamic-pituitary-adrenal (HPA) axis activity under basal and stress conditions were examined. In the first study, chronic morphine administration increased basal corticosterone levels, reduced body weight gain, increased adrenal gland weight, and decreased thymus gland weight. Rats undergoing acute (12 h) withdrawal displayed potentiated and prolonged corticosterone responses to restraint, whereas rats undergoing chronic (8 and 16 day) withdrawal displayed reduced and shorter pituitary-adrenal responses to restraint. In the second study, some of the mechanisms mediating altered HPA axis activity under basal and stress conditions in rats chronically given morphine were examined. Persistent HPA axis hyperactivity in morphine-treated rats was associated with decreased whole brain glucocorticoid receptor (GR) protein levels. Acutely withdrawn rats were insensitive to dexamethasone, suggesting that the exaggerated corticosterone responses to restraint in these animals involved impaired negative feedback systems. Acutely withdrawn rats also displayed reduced ACTH and prolonged corticosterone responses to CRH, indicating CRH receptor downregulation and enhanced adrenal sensitivity to ACTH. Rats undergoing chronic morphine withdrawal displayed enhanced pituitary-adrenal responses to dexamethasone and normal responses to CRH, thereby suggesting that reduced responsivity of the HPA axis to stress in these rats involved enhanced negative feedback sensitivity as well as blunted CRH release in response to stress. In the third study, the non-peptidic CRH-R₁ antagonist antalarmin was characterized for its potential use in the treatment of disorders, such as drug abuse, which may be associated with HPA axis hyperactivity. Although antalarmin antagonized restraint-induced increases in plasma ACTH and corticosterone levels, this compound had activating effects that might limit its use. Acute administration of antalarmin stimulated pituitary-adrenal activity and produced hypothermia; with repeated administration, tolerance developed to these activating effects. It was concluded that chronic morphine administration leads to persistent exposure of animals to stress hormones, resulting in profound and long lasting changes in the HPA axis with morphine dependence and superimposed stress conditions. Altered responsivity of the HPA axis to stressful stimuli in animals chronically exposed to the stress of morphine dependence and withdrawal could underlie the enhanced susceptibility to drug relapse in animals with a previous history of stress and drug self-injection.