A decrease in opioid tone amplifies the luteinizing hormone surge in estrogen-treated ovariectomized rats: comparisons with progesterone effects

It is well known that the estrogen-induced LH surge in ovariectomized (ovx) rats is invariably far less in magnitude than the preovulatory LH surge or that induced by progesterone (P) in estrogen-primed ovx rats. Recent studies show that a decrease in hypothalamic inhibitory opioid tone by the neural clock (NC) is responsible for the induction of the preovulatory LH surge on proestrus. Therefore, we hypothesized that the diminished LH response in estrogen-treated ovx rats may be due to an inadequate reduction in opioid tone. To test this hypothesis the effects of transiently decreasing the opioid tone with an opiate receptor antagonist, naloxone (NAL), on LH secretion in estrogen-primed, short term (5 days) and long term (4 weeks) ovx rats were examined. NAL (2 mg/h) was infused iv from 1100-1400 h on day 2 in rats receiving either sc implants (two, 15 mm each) filled with 17 beta-estradiol (300 micrograms/ml in oil) or sc estradiol benzoate (EB; 10 micrograms/rat) injections at 1000 h on day 0. For comparison of NAL- and P-induced LH responses, EB-primed short and long term ovx rats received P injection (2 mg/rat, sc) instead of NAL infusion at 1100 h. Estrogen treatment alone induced a spontaneous rise in plasma LH on the afternoon of day 2, with peak LH levels ranging between 1.5-2.4 ng/ml. NAL infusion markedly enhanced the LH surge in both groups of ovx rats. In short term ovx rats NAL-induced peak LH levels (5-6 ng/ml) were less than those observed in rats receiving supplemental P treatment or that observed previously on proestrus (10-15 ng/ml). However, in long term EB-primed ovx rats, NAL infusion evoked LH surges equivalent to those observed after P injection. In addition, analysis of the episodic LH secretion pattern showed that NAL infusion accelerated the frequency and amplitude of LH discharge and significantly changed the contour of LH episodes. These results show that a transient decrease in inhibitory opioid tone before a spontaneous LH rise in estrogen-treated ovx rats can accelerate episodic LH secretion to culminate in LH surges that resemble those induced by P and the preovulatory LH surge. Therefore, these observations are in accord with the view that the NC-induced curtailment in the inhibitory opioid tone may be inadequate in estrogen-treated rats; NAL infusion and P treatment intensify decrements in inhibitory opioid tone to reinstate the preovulatory-type LH surge in these rats.