Chronic kappa opioid receptor antagonism produces supersensitivity to U-50,488H at the hypothalamo-pituitary-adrenocortical (HPA) axis level.

The present study was conducted to evaluate the influence of chronic kappa receptor blockade on the neuroendocrine effects of the selective kappa 1 opioid agonist U-50,488H, on the hypothalamo-pituitary-adrenocortical (HPA) axis. Male Sprague-Dawley rats were chronically treated with naloxone (3 mg kg-1 day-1 for 7 days) or distilled water by s.c. implantation of osmotic minipumps and the response of the HPA axis to U-50,488H or saline was assessed before and 24 h after pump removal. Chronic infusion of naloxone reduced body weight gain and blocked the increase in corticosterone secretion induced by U-50,488H, indicating occupation of kappa opioid receptors. Significantly higher plasma corticosterone levels after U-50,488H administration at doses of 5 or 15 mg/kg were observed 1 day after cessation of naloxone treatment compared with those in corresponding control rats. The enhanced responsiveness of the HPA axis to U-50,488H (15 mg/kg) was antagonized by norbinaltorphimine (5 mg/kg), suggesting a role for kappa receptors in mediating supersensitivity to the kappa agonist. The findings of the present study demonstrated that chronic blockade of the kappa receptor results in augmentation of kappa agonist-induced stimulation of the HPA axis activity (functional supersensitivity).