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Department of Physiology and Pharmacology, Oregon Health Sciences
University, Portland, Oregon 97201
17
-Estradiol (E2) rapidly (<20 min) attenuates the
ability of µ-opioids to hyperpolarize guinea pig hypothalamic
(-endorphin) neurons. In the current study, we used intracellular
recordings from guinea pig hypothalamic slices to characterize the
receptor and intracellular effector system mediating the rapid effects of E2. E2 acted stereospecifically with
physiologically relevant concentration dependence (EC50 = 8 nM) to cause a 4-fold reduction in the potency of a
µ-opioid agonist to activate an inwardly rectifying K+
conductance. Using Schild analysis to estimate the affinity of the
µ-opioid receptor for an antagonist (naloxone), we found that estrogen did not compete for the µ-opioid receptor or alter the affinity of the µ receptor. Both the nonsteroidal estrogen
diethylstilbestrol and the "pure" antiestrogen ICI 164,384 blocked
the actions of E2, the latter with a subnanomolar affinity.
The protein synthesis inhibitor cycloheximide did not block the
estrogenic uncoupling of the µ-opioid receptor from its
K+ channel, implying a nongenomic mechanism of action by
E2. The actions of E2 were mimicked by the
protein kinase A (PKA) activators forskolin and cAMP, Sp-isomer
triethylammonium salt. Furthermore, the selective PKA antagonists cAMP,
Rp-isomer triethylammonium salt and KT5720, which have different
chemical structures and modes of action, both blocked the effects of
E2. Thus, estrogen binds to a specific receptor that
activates PKA to rapidly uncouple the µ-opioid receptor from its
K+ channel. Because we have previously shown that
-aminobutyric acidB receptors are also uncoupled by
estrogen, this mechanism of action has the potential to alter synaptic
transmission via G protein-coupled receptors throughout the brain.
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