The -opioid receptor ( -OR), like most G-protein-coupled receptors, is rapidly internalized after agonist binding. Although opioid peptides induce internalization in vivo, there are no studies that demonstrate -OR internalization in response to natural stimuli. In this study, we used laser-scanning microscopy to demonstrate that estrogen treatment induces the translocation of -OR immunoreactivity ( -ORi) from the membrane to an internal location in steroid-sensitive cell groups of the limbic system and hypothalamus. Estrogen-induced internalization was prevented by the opioid antagonist naltrexone, suggesting that translocation was largely dependent on release of endogenous agonists. Estrogen treatment also altered the pattern of -ORi at the bright-field light microscopic level. In the absence of stimulation, the majority of immunoreactivity is diffuse, with few definable -ORϩ cell bodies or processes. After stimulation, the density of distinct processes filled with -ORi was significantly increased. We interpreted the increase in the number of -ORϩ processes as indicating increased levels of internalization. Using this increase in the density of -ORϩ fibers, we showed that treatment of ovariectomized rats with estradiol benzoate induced a rapid and reversible increase in the number of fibers. Significant internalization was noted within 30 min and lasted for Ͼ24 hr after estrogen treatment in the medial preoptic nucleus, the principal part of the bed nucleus, and the posterodorsal medial amygdala. Naltrexone prevented the increase of -ORϩ processes. These data imply that estrogen treatment stimulates the release of endogenous opioids that activate -OR in the limbic system and hypothalamus providing a "neurochemical signature" of steroid activation of these circuits.

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