Age-related differences in the sensitivity of serum luteinizing hormone to prototypic mu, kappa and delta opiate agonists and antagonists

It has been shown in developing male rats that morphine maximally depresses serum luteinizing hormone (LH) levels as early as postnatal day 15. In contrast, naloxone fails to increase serum LH in the prepubescent male rat but, coincident with the onset of puberty (30-35 days of age), the antagonist becomes increasingly more effective until adult appropriate responses are achieved at sexual maturation. The purpose of the present studies was to examine and characterize further the dichotomous response to naloxone and morphine in the prepubescent male rat. We found that the inability of naloxone to affect a release in LH-releasing hormone (LHRH) was not related to pharmacokinetic factors as the dose and time-response characteristics were identical in young and adult animals. In addition, our results indicated that the release of LHRH and its actions on the pituitary to promote LH release were equivalent in prepubescent and adult rats, indicating that if naloxone was capable of releasing LHRH then robust increases in LH should have occurred. Our results indicate further that the ineffectiveness of naloxone in prepubescent animals was not unique to this compound inasmuch as kappa antagonists also were devoid of activity in young animals but were highly effective in adults; delta opiate antagonists failed to increase LH either in young or adult animals. In contrast to these data, we observed that mu and kappa agonists were equipotent in depressing serum LH levels in both young and adult animals. Our data are consistent with one of two interpretations: either naloxone has no affinity for the receptor subtype involved in LHRH release in the prepubescent animal or the endogenous ligand for this receptor is absent until the onset of puberty. Nevertheless, our results suggest that the maturation of the endogenous opioid peptide-containing neuronal systems which govern LHRH release are in some way linked to the onset of puberty and sexual maturation. Whether this relationship is causal or simply correlational in nature remains to be determined.