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 activity in developing rat pups (first and second weeks of postnatal life). The second aim of this study was to explore, in vivo, if nitric oxide (NO) could be involved in the neurohormonal response to morphine in the early stages of postnatal life.


METHODS
Plasma ACTH and corticosterone concentrations were determined by RIA in rat pups (n=5-14 rats/experimental group) after they had been killed 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 pretreated s.c. with naltrexone (NAL; 0.4 mg/kg or 10 mg/kg), and injected 1 h later with either morphine (20 mg/kg) or vehicle, and killed 30 min later. Some 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 l arginine methyl-ester (L-NAME; 30 mg/kg or 100 mg/kg), and injected 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 injected 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 ACTH and corticosterone secretion. Moreover, these responses increased with advancing postnatal age. In 2-week-old rat pups, NAL, a competitive antagonist at mu-opioid receptors, administered alone increased both plasma ACTH and corticosterone concentrations 30 min later. L-NAME, a specific NO synthase inhibitor, did not affect plasma ACTH and corticosterone concentrations 30 min later when administered alone. NAL, when concomitantly administered with morphine, was unable to block morphine responses. In contrast, morphine responses were blocked by pretreatment (60 min before) with NAL or with L-NAME. Acute injection of SNAP increased both ACTH and corticosterone release.


CONCLUSIONS
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.
Laboratoire de Neuroendocrinologie du Developpement, UPRES-EA 2701, Universite de Lille 1, Bat. SN4, 59655 Villeneuve d'Ascq, France. jlesage@univ-lille1.fr
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Lesage
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Bernet
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Montel
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Dupouy
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D003345:Corticosterone / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical
D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D009020:Morphine; D000324:Adrenocorticotropic Hormone; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D003345:Corticosterone