Morphine-induced stimulation of pituitary-adrenocortical activity is mediated by activation of nitric oxide in the early stages of postnatal life in the rat

Objective: The first aim of the present study was to determine if morphine, a prototypic mu -opioid agonist drug, affects pituitary-adrenocortical act ivity in developing rat pups (first and second weeks of postnatal life). Th e second aim of this study was to explore, in vivo, if nitric oxide (NO) co uld be involved in the neurohormonal response to morphine in the early stag es of postnatal life. Methods: Plasma ACTH and corticosterone concentrations were determined by R IA in rat pups (n = 5-14 rats/experimental group) after they had been kille d by decapitation. In a first experiment, 1-day and 1- and 2-week-old rats were treated s.c. with morphine (20 mg/kg) or with vehicle (0.9% NaCl) and killed 5-90 min later. In a second experiment, 2-week-old pups were pretrea ted s.c. with naltrexone (NAL: 0.4 mg/kg or 10 mg/kg), and injected 1 h lat er with either morphine (20 mg/kg) or vehicle, and killed 30 min later. Som e pups injected with only NAL were killed 60 or 90 min later. On the other hand, pups injected with NAL (10 mg/kg) or NAL and morphine were killed 30 min later. In a third experiment, 2-week-old pups were pretreated s.c, with N-omega -nitro arginine methylester (L-NAME: 30 mg/kg or 100 mg/kg), and i njected 1 h later with either morphine (20 mg/kg) or vehicle, and killed 30 min later. Moreover, some pups injected with L-NAME (100 mg/kg) or L-NAME with morphine were killed 30 min later. In a final experiment, pups were in jected s.c. with either S-nitroso-N-acetylpenicillamine (SNAP: 5 mg/kg) or vehicle, and killed 60 or 90 min later, Results: Morphine administered to rat pups elicited marked rises in both AC TH and corticosterone secretion. Moreover, these responses increased with a dvancing postnatal age. In 2-week-old rat pups, NAL, a competitive antagoni st at mu -opioid receptors, administered alone increased both plasma ACTH a nd corticosterone concentrations 30 min later, L-NAME, a specific NO syntha se inhibitor, did not affect plasma ACTH and corticosterone concentrations 30 min later when administered alone. NAL, when concomitant-ly administered with morphine, was unable to block morphine responses. In contrast, morphi ne responses were blocked by pretreatment (60 min before) with NAL or with L-NAME, Acute injection of SNAP increased both ACTH and corticosterone rele ase. Conclusion: Our results suggest that opioids have controversial effects on pituitary-adrenocortical activity in the early postnatal period in the rat, and that endogenous NO is one of the major factors in the response of the pituitary-adrenocortical axis to morphine.