Opiatergic control of gonadotropin secretion during puberty in the rat: a neurochemical basis for the hypothalamic 'gonadostat'?

We have examined (1) the effects of naloxone and an opiate peptide, FK 33-824, on LH and FSH secretion in immature male and female rats and (2) the influence of sexual maturation on the ability of this peptide to inhibit LH secretion. FK 33-824 potently inhibits LH secretion in the 48-h-gonadectomized rat. This effect could be blocked by coinjection of naloxone, suggesting that the peptide exerts its influence through opiate receptors. An endogenous opiate component in the control of LH secretion was demonstrated by examining the effect of naloxone injection alone. Naloxone rapidly stimulated LH secretion in the intact or the acutely gonadectomized rat. Naloxone or FK 33-824 did not modify LHRH-stimulated release of gonadotropins from organ cultures of anterior pituitary obtained from immature rats. This suggests, in agreement with other reports, that naloxone or FK 33-824 controls LH secretion via a central, possibly hypothalamic site. We further observed a clear age-related reduction in LH sensitivity to FK 33-824 in the acutely (48-h) gonadectomized rat. Dose-response studies indicated a 4-fold reduction in opiate responsiveness in the 10 days preceding the first ovulation. Thus, the doses required to reduce serum LH levels by 50% are 0.03, 0.04, 0.16, and 0.17 mg/kg, respectively, for the groups 12, 23, 29, and 33 days of age. In the male, a similar change was noted when responsiveness was compared in pre- and postpubertal rats; 50% inhibition was achieved at 0.25, 0.89, and 0.88 mg/kg FK 33-824 for rats aged 26, 70, and 90 days, respectively. The shift in sensitivity to FK 33-824 is probably not due to a change in clearance rates, but this cannot be completely ruled out. Thus, our demonstration of a maturation-related reduction in opiate inhibition of LH suggests a critical role for endogenous (hypothalamic?) opiate peptides and opiate receptors in the onset of sexual maturation. Our results may also provide a neurochemical basis for the well described shift in hypothalamic sensitivity to gonadal steroids that occurs with the approach of puberty.