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Activation of c-fos Expression in Hypothalamic Nuclei by µ- and -Receptor Agonists: Correlation with Catecholaminergic Activity in the Hypothalamic Paraventricular Nucleus¹

Department of Physiology and Pharmacology, Unit of Pharmacology (M.L.L., M.D.M., P.J.M., M.V.M.), and Department of Cell Biology (M.T.C.), University School of Medicine, 30100 Murcia, Spain

Address all correspondence and requests for reprints to: Dr. M. V. Milanés, Unit of Pharmacology, School of Medici School of Medicine, 30100 Murcia, Spain. E-mail: milanes{at}fcu.um.es

Administration of the preferential µ-opioid receptor agonist, morphine, and selective -opioid receptor agonists elicits activation of the hypothalamus-pituitary-adrenocortical axis, although the site or the molecular mechanisms for these effects have not been determined. The expression of Fos, the protein product of the c-fos protooncogene, has been widely used as an anatomical marker of monitoring neuronal activity. In the present study we evaluated 1) the effects of the µ-opioid receptor agonist, morphine, and those of the selective -opioid receptor agonist, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl-]benzeneacetamide methane sulfonate (U-50,488H), administration on the expression of Fos in hypothalamic nuclei; and 2) the possible modification of the activity of noradrenergic neurons known to send afferent projections to the paraventricular nucleus (PVN), the site of CRF neurons involved in initiating ACTH secretion. Using immunohistochemical staining of Fos, the present results indicate that acute treatment with either morphine or U-50,488H induces marked Fos immunoreactivity within the hypothalamus, including the medial parvicellular PVN and supraoptic and suprachiasmatic nuclei. Pretreatment with naloxone attenuated the effect of morphine, whereas nor-binaltorphimine, a selective -opioid receptor antagonist, abolished the effect of U-50,488H on Fos induction. Correspondingly, morphine and U-50,488H injection increased the production of the cerebral noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol as well as noradrenaline turnover in the PVN. These effects were antagonized by naloxone and nor-binaltorphimine, respectively. All of these findings are discussed in terms of specific events that couple opioid-induced activation of the hypothalamus-pituitary-adrenocortical axis and noradrenergic activity with changes in gene expression in selective hypothalamic nuclei.

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