ESTRADIOL-17-BETA AND MU-OPIOID PEPTIDES RAPIDLY HYPERPOLARIZE GNRH NEURONS - A CELLULAR MECHANISM OF NEGATIVE FEEDBACK

Control of the HPG axis involves a rapid (30 min) inhibition of LH (GnRH) release by E(2). The time course of this effect is faster than expected for a purely transcriptional mechanism of E(2) action. To elucidate the mechanism of E(2) action, intracellular recordings in TTX were performed in guinea pig hypothalamic GnRH neurons. These neurons were directly hyperpolarized by both the mu-opioid agonist, DAMGO (Tyr-D-Ala-Gly-MePhe-Gly-ol, 9 mV) and the GABA(B) agonist, baclofen (18 mV) by opening K+ channels. Schild analysis with naloxone (K-e=2.4 nM) confirmed that mu-opioid receptors mediated the effect of DAMGO. E(2) also directly hyperpolarized GnRH neurons by opening K+ channels. Coupled with previous work showing a rapid effect of E(2) to alter mu-opioid potency (1), a model is presented in which E(2) rapidly inhibits GnRH neurons through parallel, possibly synergistic pathways.