The Journal of Neuroscience, August 1, 2001, 21(15):5723-5729
Progesterone Blockade of Estrogen Activation of µ-Opioid
Receptors Regulates Reproductive Behavior
Kevin
Sinchak and
Paul E
Micevych
Department of Neurobiology, Mental Retardation Research Center and
Laboratory of Neuroendocrinology, Brain Research Institute, University
of California, Los Angeles, School of Medicine, Los Angeles, California
90095-1763
The µ-opioid receptor (MOR), a G-protein-coupled receptor, is
internalized after endogenous agonist binding. Although receptor activation and internalization are separate events, internalization is
a good assay for activation because endogenous opioid peptides all
induce internalization. Estrogen treatment of ovariectomized rats
induces MOR internalization, providing a neurochemical signature of
estrogen activation of the medial preoptic nucleus. MOR activation appears to be the mechanism via which estrogen acts in the medial preoptic area to prevent the display of female reproductive behavior during the first 20-24 hr after estrogen treatment.
Naltrexone, an alkaloid universal opioid receptor antagonist, prevented
MOR internalization, suggesting that estrogen induces the release of
endogenous opioid peptides that in turn activate the MOR. Enkephalins and 
-endorphin are nonselective endogenous MOR ligands. The most selective endogenous MOR ligands are the endomorphins. Infusions of
selective MOR agonists,
H-Tyr-D-Ala-Gly-N-Met-Phe-glycinol-enkephalin (DAMGO) or endomorphin-1, into the medial preoptic nucleus attenuated lordosis, and their effects were blocked with the MOR antagonist H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2
(CTOP). Infusion of endomorphin-1 internalized MOR. To determine
whether progestin also acts via the MOR system to facilitate
reproductive behavior, ovariectomized rats were primed with
17-estradiol and progesterone. Progestin facilitation of
lordosis was correlated with a reduction of estrogen-induced MOR
internalization. Progestin reversed estrogen-induced MOR
internalization, suggesting that progesterone blocked estrogen-induced endogenous opioid release, relieving estrogen inhibition and
facilitating lordosis. These results indicate a central role of MOR in
the mediation of sex steroid activation of the CNS to regulate
female reproductive behavior.
Key words:
sexual receptivity; CTOP; DAMGO; endomorphin-1; G-protein-coupled receptors; medial preoptic nucleus
Copyright © 2001 Society for Neuroscience 0270-6474/01/21155723-07$05.00/0
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