DIURNAL ALTERATION IN OPIATE EFFECTS ON THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS - CHANGES IN THE MECHANISM OF ACTION

Opioid control of the hypothalamo-pituitary-adrenocortical axis has a characteristic circadian rhythm (Kiem, Kanyicska, Stark and Fekete, 1987). To elucidate the mechanisms leading to circadian alterations of opioid control of the hypothalamo-pituitary-adrenocortical axis, and to look for the receptor type at which the p.m. inhibitory action of opioids occurs, we examined the effect of morphine at different doses and the interaction between naloxone and morphine at different times of day in intact male Wistar rats. In the morning: morphine (10 and 30 mg/kg s.c.) significantly increased corticosterone secretion, while 3 mg/kg s.c. had no effect. Naloxone in a dose of 2.5 mg/kg i.p. significantly antagonized the corticosterone-releasing effect of morphine, suggesting that the secretion of corticosterone induced by morphine is mediated via mu-opioid receptors. In the afternoon: basal plasma corticosterone levels were higher than those in the morning, and morphine caused a significant corticosterone increase only at the dose of 30 mg/kg, and had no effect in the dose of 10 mg/kg. Morphine significantly decreased corticosterone levels in the dose of 3 mg/kg. This inhibitory action lasted approximately 3 h after morphine injection and was able to inhibit the circadian evening rise of corticosterone. The effect of morphine and the interaction between naloxone and morphine on prolactin secretion remained unchanged from a.m, to p.m.; naloxone (2.5 mg/kg i.p.) which inhibited the 30 mg/kg morphine-induced corticosterone rise in the morning failed to antagonize the 3 mg/kg morphine-induced decrease of corticosterone secretion in the afternoon. A high dose of naloxone (10 mg/kg i.p.) effectively prevented the 3 mg/kg morphine-induced p.m. inhibition of corticosterone secretion. The results of this study point to dual mechanism(s) of opioid action on the hypothalamopituitary-adrenal axis: the a.m. stimulatory mechanism is naloxone-sensitive, while the p.m. inhibitory mechanisms is naloxone-resistant.