The present study investigated the effect of highly selective mu-opioid receptor (OR) agonists on lordosis behavior in ovariectomized rats treated with 3 microg of estradiol benzoate followed 48 h later by 200 microg of progesterone. Ventricular infusion of the endogenous mu-OR agonists endomorphin-1 and -2 suppressed receptive behavior in a time- and dose-dependent fashion. At 6 microg, both endomorphin-1 and -2 inhibited lordosis behavior within 30 min. However, while the effect of endomorphin-1 lasted 60 min, endomorphin-2 inhibition lasted up to 120 min after infusion. Pretreatment with naloxone (5 mg/kg sc) was able to block both endomorphin-1 and endomorphin-2 effects on lordosis. Site-specific infusions of endomorphin-1 or endomorphin-2 into the medial preoptic area (mPOA), the ventromedial nucleus of the hypothalamus (VMH), or into the mesencephalic central gray did not affect receptivity. In contrast, infusion of 1 mug of either compound into the medial septum/horizontal diagonal band of Broca inhibited lordosis in a pattern very similar to that seen after intraventricular infusions. Infusion of the potent synthetic mu-OR agonist [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin (0.08 microg) into the VMH and mPOA inhibited lordosis behavior for at least 60 min after infusion. The nonspecific opioid receptor antagonist naloxone was able to facilitate lordosis in partially receptive female rats when infused into the mPOA but not when infused into the VMH. The behavioral effects of the agonists and antagonist used in this study suggest that the endogenous mu-opioid system modulates estrogen and progesterone-induced lordosis behavior.