Naloxone does not reverse the inhibitory effect of morphine on luteinizing hormone secretion in prepubescent male rats

Morphine and naloxone exert age-dependent effects on secretion of luteinizing hormone (LH) in the male rat. Morphine suppresses LH secretion at very early stages of development, well before puberty, whereas naloxone does not increase LH until after puberty. The mechanisms underlying these age-dependent effects of opiates on the hypothalamic-pituitary-gonadal axis in pre- and postpubertal rats are poorly understood at the present time. The purpose of the present studies was to examine one plausible explanation of these effects: that morphine and naloxone act through different receptors in the pubescent male rat than they do in adults to influence LH secretion. Specifically, we examined whether naloxone blocks the effects of morphine on LH in prepubescent and adult rats which would be anticipated if both drugs were exerting their effects on LH via the same opiate receptor. Surprisingly, we found that naloxone did not reverse the effects of morphine on serum LH levels in the prepubescent animal, although it fully reversed this effect in adults. This non-naloxone-reversible effect of morphine appeared to be specific to LH, since naloxone antagonized morphine's effects on several other hormones (e.g., prolactin and corticosterone) and completely attenuated morphine's antinociceptive activity in prepubescent rats. Additionally, naloxone precipitated a withdrawal syndrome in the prepubescent morphine-dependent animal that was quantitatively and qualitatively the same as in adults. Consequently, these data suggest that naloxone can compete with morphine at those receptors involved in several neuroendocrine systems, analgesia and physical dependence, but apparently cannot reverse the effects of morphine at those sites involved in the regulation of luteinizing hormone releasing hormone/LH secretion, at least in the prepubescent rat. Our data illustrate perhaps one of the most clear-cut examples of a naloxone-irreversible effect of morphine. The mechanisms involved in this effect are unclear, but further support the hypothesis that the onset of puberty and sexual maturation are characterized by marked differences in the response of the hypothalamic-pituitary-gonadal axis to opiate agonists and antagonists and the endogenous opioid peptide- mediated control of reproductive endocrinology.