Hypothalamic opioid peptides have been implicated in the timing of sexual maturation in several species. We have examined the effects of neonatal opioid blockade on the timing of puberty in the female rat and have compared these with the effects of neonatal GnRH injection. Intermittent naloxone (2·5 mg/kg) or GnRH (200 ng/100 g body wt) injected s.c. at 6-h intervals for the first 10 days of life only slightly advanced the mean day of vaginal opening (VO). However, the degree of precocity was significantly more marked in a subgroup of drug-injected rats. In contrast, injections of the long-acting opioid antagonist naltrexone (50 mg/kg) had no effect on the timing of VO.
The results suggested that the duration of opioid receptor blockade is critical in determining the degree of opioid antagonist effect. Therefore, additional studies were performed to compare receptor occupancy of naloxone and naltrexone in 9-day-old rat pups. An exvivo binding assay was utilized to determine the availability of hypothalamic opioid-binding sites at various intervals following a single s.c. injection of antagonist. The time-course of inhibition of tritium labelled [d-Ala2-N-Me-Phe4,Gly5-ol]-enkephalin ([3H]DAGO) binding (μ-opioid sites) revealed that naloxone occupies the μ-receptor for a relatively short period of time. Naloxone (2·5 and 50 mg/kg) produced extensive inhibition of [3H]DAGO binding at 30 min following injection but binding was 100% of control at 1 h and 3·5 h respectively. In contrast, hypothalamic binding in naltrexone-treated (50 mg/kg) pups did not reach 50% of control values until 12 h and 100% of control values at 20 h after injection. The results are consistent with naltrexone's role as a long-acting antagonist but indicate that this blockade is not sustained for 24 h as previously indicated by indirect assessment with opiate challenge tests. Our data demonstrate that the duration of μ-opioid receptor occupancy is an important consideration in attempting to understand why intermittent, but not more continuous, blockade of opioid receptors induces some degree of sexual precocity in female rats. Also of interest is the observation that anterior pituitary stimulation with GnRH, during the first 10 days of life, can modify the timing of sexual maturation.
J. Endocr. (1988) 119, 447–452
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