Progesterone blockade of estrogen activation of mu-opioid receptors regulates reproductive behavior

The mu -opioid receptor (MOR), a G-protein-coupled receptor, is internalize d after endogenous agonist binding. Although receptor activation and intern alization are separate events, internalization is a good assay for activati on because endogenous opioid peptides all induce internalization. Estrogen treatment of ovariectomized rats induces MOR internalization, providing a n eurochemical signature of estrogen activation of the medial preoptic nucleu s. MOR activation appears to be the mechanism via which estrogen acts in th e medial preoptic area to prevent the display of female reproductive behavi or during the first 20-24 hr after estrogen treatment. Naltrexone, an alkal oid universal opioid receptor antagonist, prevented MOR internalization, su ggesting that estrogen induces the release of endogenous opioid peptides th at in turn activate the MOR. Enkephalins and beta -endorphin are nonselecti ve endogenous MOR ligands. The most selective endogenous MOR ligands are th e 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 an tagonist H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP). Infusion of endo morphin-1 internalized MOR. To determine whether progestin also acts via th e MOR system to facilitate reproductive behavior, ovariectomized rats were primed with 17 beta -estradiol and progesterone. Progestin facilitation of lordosis was correlated with a reduction of estrogen-induced MOR internaliz ation. Progestin reversed estrogen-induced MOR internalization, suggesting that progesterone blocked estrogen-induced endogenous opioid release, relie ving 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.