CHRONIC NALOXONE-INDUCED SUPERSENSITIVITY AFFECTS NEITHER TOLERANCE TO NOR PHYSICAL-DEPENDENCE ON MORPHINE AT HYPOTHALAMUS PITUITARY-ADRENOCORTICAL AXIS

This study reports the endocrine effects of chronic mu-blockade induce d by naloxone on morphine tolerance and withdrawal at hypothalamus-pit uitary-adrenocortical (HPA) axis level. Naloxone (0.5 mg/kg/h) or vehi cle (1 mu l/h) were infused s.c. to Sprague-Dawley rats via osmotic mi nipumps for 7 days, concomitantly with morphine or placebo pellets for 7-8 days. In opiate-naive rats, the mu-preferring opioid agonist morp hine (30 mg/kg) increased plasma corticosterone in a partial but signi ficant naloxone-reversible manner. In vehicle-perfused rats, chronic m orphine treatment produced tolerance to its neuroendocrine effect, whi le the development of morphine tolerance was antagonized in the naloxo ne-treated group. An enhancement of plasma corticosterone levels after acute morphine (30 mg/kg) occurred 24 h after removal of chronic nalo xone treatment in vehicle-perfused rats, as a functional index of supe rsensitivity to the neuroendocrine effects of the mu agonist. By contr ast, 24 h after naloxone removal, rats implanted with morphine pellets were significantly less sensitive to acute morphine (tolerance) than its control-placebo group. Substantial elevation of plasma corticoster one, accompanied by motor and behavioural signs, was observed after ac ute naloxone injection (1 mg/kg) to tolerant rats 24 h after naloxone- pumps removal, which indicates withdrawal. No endocrine, motor or beha vioural signs appeared in the naloxone group with pumps in place. Thes e results indicated that morphine desensitizes mu-opioid receptors tha t were probably upregulated by chronic naloxone in presence of chronic agonist administration, and suggest that opioid tolerance/dependence as well as opioid supersensitivity simultaneously and independently ca n occur at mu-opioid receptors mediating HPA function.