Estrogen-induced alteration of mu-opioid receptor immunoreactivity in the medial preoptic nucleus and medial amygdala.
The mu-opioid receptor (mu-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 mu-OR internalization in response to natural stimuli. In this study, we used laser-scanning microscopy to demonstrate that estrogen treatment induces the translocation of mu-OR immunoreactivity (mu-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 mu-ORi at the bright-field light microscopic level. In the absence of stimulation, the majority of immunoreactivity is diffuse, with few definable mu-OR+ cell bodies or processes. After stimulation, the density of distinct processes filled with mu-ORi was significantly increased. We interpreted the increase in the number of mu-OR+ processes as indicating increased levels of internalization. Using this increase in the density of mu-OR+ 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 >24 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 mu-OR+ processes. These data imply that estrogen treatment stimulates the release of endogenous opioids that activate mu-OR in the limbic system and hypothalamus providing a "neurochemical signature" of steroid activation of these circuits.
Eckersell
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CB
Department of Neurobiology, School of Medicine, and the Laboratory of Neuroendocrinology, Brain Research Institute, University of California Los Angeles, Los Angeles, California 90095-1763, USA.
Popper
P
P
Micevych
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PE
D000679:Amygdala / Q000737:chemistry* / Q000187:drug effects; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000918:Antibody Specificity; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018847:Opioid Peptides / Q000378:metabolism; D010052:Ovariectomy; D011301:Preoptic Area / Q000737:chemistry* / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D014316:Tritium
D000701:Analgesics, Opioid; D004745:Enkephalins; D004967:Estrogens; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009271:Naltrexone; D019204:GTP-Binding Proteins