Chronic naloxone-induced supersensitivity affects neither tolerance to nor physical dependence on morphine at hypothalamus-pituitary-adrenocortical axis

Abstract This study reports the endocrine effects of chronic μ-blockade induced by naloxone on morphine tolerance and withdrawal at hypothalamus-pituitary-adrenocortical (HPA) axis level. Naloxone (0.5 mg/kg/h) or vehicle (1 μl/h) were infused s.c. to Sprague-Dawley rats via osmotic minipumps for 7 days, concomitantly with morphine or placebo pellets for 7–8 days. In opiate-naive rats, the μ-preferring opioid agonist morphine (30 mg/kg) increased plasma corticosterone in a partial but significant naloxone-reversible manner. In vehicle-perfused rats, chronic morphine treatment produced tolerance to its neuroendocrine effect, while the development of morphine tolerance was antagonized in the naloxone-treated group. An enhancement of plasma corticosterone levels after acute morphine (30 mg/kg) occurred 24 h after removal of chronic naloxone treatment in vehicle-perfused rats, as a functional index of supersensitivity to the neuroendocrine effects of the μ agonist. By contrast, 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 corticosterone, accompanied by motor and behavioural signs, was observed after acute naloxone injection (1 mg/kg) to tolerant rats 24 h after naloxone-pumps removal, which indicates withdrawal. No endocrine, motor or behavioural signs appeared in the naloxone group with pumps in place. These results indicated that morphine desensitizes μ-opioid receptors that 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 can occur at μ-opioid receptors mediating HPA function.