The potency of μ-opioid hyperpolarization of hypothalamic arcuate neurons is rapidly attenuated by 17β-estradiol

The μ-opioid agonist DAMGO (Tyr-D-Ala-Gly-MePhe-Gly-ol) hyperpolarizes the majority of arcuate hypothalamic (ARC) neurons by opening an inwardly rectifying potassium conductance. The EC₅₀ for the DAMGO-induced hyperpolarization was 60 ± 3 nM in ARC neurons from ovariectomized guinea pigs. Superfusion of 17β-estradiol (E₂; 100 nM) for 20 min in vitro resulted in a significant decrease in DAMGO potency (EC₅₀ = 212 ± 16 nM) in 40% of the neurons that were tested. This rapid effect of E₂ on the μ- opioid response was not mimicked by the biologically inactive isomer 17α- estradiol. Multiple concentrations of E₂ were used to generate an E₂ concentration-response curve, with an EC₅₀ of 9 nM and a maximal increase in the DAMGO EC₅₀ of 411% of controls. The membrane properties and firing rate of E₂-sensitive and E₂-insensitive neurons were not different. Streptavidin-FITC labeling did not reveal any significant morphological differences between the groups, but a higher number of E₂-sensitive cells was found in the lateral ARC and cell-poor zone. Moreover, immunocytochemical staining of the recorded cells revealed that β-endorphin neurons were among those sensitive to E₂. Therefore, E₂ could increase β-endorphin release by decreasing the potency of β-endorphinergic autoinhibition, thus increasing the tonic opioid inhibition of E₂-insensitive cells. Furthermore, the diffuse projections of hypothalamic β-endorphin neurons would allow E₂ to alter processes throughout the brain, as well as having local effects in the hypothalamus.