Activation of c-fos expression in hypothalamic nuclei by mu- and kappa-receptor agonists: Correlation with catecholaminergic activity in the hypothalamic paraventricular nucleus

Administration of the preferential mu-opioid receptor agonist, morphine, an d selective kappa-opioid receptor agonists elicits activation of the hypoth alamus-pituitary-adrenocortical axis, although the site or the molecular me chanisms 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 mu-opioid receptor agonist, morphine, and those of the selective kappa-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 nucle i; and 2) the possible modification of the activity of noradrenergic neuron s known to send afferent projections to the paraventricular nucleus (PVN), the site of CRF neurons involved in initiating ACTH secretion. Using immuno histochemical staining of Fos, the present results indicate that acute trea tment with either morphine or U-50,488H induces marked Fos immunoreactivity within the hypothalamus, including the medial parvicellular PVN and suprao ptic and suprachiasmatic nuclei. Pretreatment with naloxone attenuated the effect of morphine, whereas nor-binaltorphimine, a selective kappa-opioid r eceptor antagonist, abolished the effect of U-50,4888H on Fos induction. Co rrespondingly, morphine and U-50,488H injection increased the production of the cerebral noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene gl ycol as well as noradrenaline turnover in the PVN. These effects were antag onized by naloxone and nor-binaltorphimine, respectively. All of these find ings are discussed in terms of specific events that couple opioid-induced a ctivation of the hypothalamus-pituitary-adrenocortical axis and noradrenerg ic activity with changes in gene expression in selective hypothalamic nucle i.