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 (Gn RH) release by E(2). The time course of this effect is faster than exp ected for a purely transcriptional mechanism of E(2) action. To elucid ate 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-A la-Gly-MePhe-Gly-ol, 9 mV) and the GABA(B) agonist, baclofen (18 mV) b y opening K+ channels. Schild analysis with naloxone (K-e=2.4 nM) conf irmed 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 p otency (1), a model is presented in which E(2) rapidly inhibits GnRH n eurons through parallel, possibly synergistic pathways.