Sex-related differences in the sensitivity to pain and in the response to analgesics have been reported including higher perceptual responses to experimentally induced pain and the higher prevalence of many pain syndromes in women compared with men. This study examines whether alpha2-adrenoceptor-mediated antinociceptive effects are reduced by estrogen which could account for the sex-related differences in pain perception and modulation. Clonidine, an alpha2-adrenoceptor agonist, has been shown to inhibit noxious stimulus-evoked nociceptive behavior as well as the responses of nociceptive neurons in the medullary dorsal horn. Intracisternal microinjection of clonidine (7 microg/5 microl) through the implanted PE-10 cannulae dorsal to the trigeminal region in male, ovariectomized (OVX), and diestrous (DiE) Sprague-Dawley rats produced a strong antinociceptive effect on N-methyl-D-aspartic acid (NMDA)-induced nociceptive scratching behavior and heat-induced face withdrawal nociceptive tests. However, it failed to produce any inhibition in the estradiol-treated ovariectomized (OVX+E) group regardless of the dose of estradiol (1, 10 or 100 microg/100 microl sesame oil) or in the proestrous (ProE) group. Further, clonidine produced dose-dependent effects in male and OVX groups but not in the OVX+E group on the NMDA-induced nociceptive behavior. Finally, the effect of clonidine was reversed by yohimbine, an alpha2-adrenoceptor antagonist, in male and OVX groups on thermal nociceptive test. These results lead us to conclude that activation of alpha2-adrenoceptors produces sex-specific, estrogen dependent modulation of nociception in the trigeminal region of the rat. A decreased alpha2-adrenoceptor-mediated inhibition could be one of the factors responsible for the higher prevalence of pain syndromes in females.