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

Abstract

Administration of the preferential mu-opioid receptor agonist, morphine, and selective K-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 ofFos, 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 K-opioid receptor agonist, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl-]benzeneacet amide 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 kappa-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-bin-altorphimine, 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.

κ Agonist-Induced Reinstatement of Cocaine Seeking in Squirrel Monkeys: A Role for Opioid and Stress-Related Mechanisms

“…Dynorphin, which plays a role in regulating the stress response, is colocalized with CRF in the paraventricular nucleus of the hypothalamus (Roth et al, 1983) and has been found to modulate the effects of CRF on autonomic function (Overton and Fisher, 1989). Agonists also increase CRF release (Buckingham and Cooper, 1986) and stimulate the hypothalamic-pituitary-adrenal axis (Ur et al, 1997;Laorden et al, 2000). In light of these findings, it seems possible that priming with spiradoline in our study led to downstream activation of brain CRF 1 systems involved in the regulation of stress.…”

“…Opioids have been shown to enhance NE turnover in the paraventricular nucleus of the hypothalamus (Laorden et al, 2000), increase NE metabolism in the brain stem and cortex (Kunihara et al, 1992), and stimulate NE release in the hippocampus (Jackisch et al, 1986). In addition, the NE transport inhibitor, imipramine, enhances spiradoline-induced analgesia (Kunihara et al, 1992).…”

“…Agonists stimulate the hypothalamic-pituitary-adrenal axis in rodents (Laorden et al, 2000) and humans (Ur et al, 1997), which is primarily regulated by CRF release in the hypothalamus (Vale et al, 1983). Within the noradrenergic system, agonists increase NE turnover in the paraventricular nucleus of the hypothalamus (Laorden et al, 2000) and NE release in the hippocampus (Jackisch et al, 1986).…”

Differential effects of stress and amphetamine administration on Fos‐like protein expression in corticotropin releasing factor‐neurons of the rat brain

“…Thus, cocaine does not induced c-fos expression in this area (Torres and Rivier, 1994;Chang et al, 1995). whereas cannabinoids, opioids, alcohol and nicotine do (Chang et al, 1995;Valentine et al, 1996;Matta et al, 1997;Wenger et al, 1997;Laorden et al, 2000), although there is only evidence for c-fos expression in CRF+ neurons in the case of nicotine (Matta et al, 1997).…”

Effects of Corticotropin-Releasing Factor Receptor-1 Antagonists on the Brain Stress System Responses to Morphine Withdrawal

“…NA and its metabolite in the central nervous system, 3-methoxy-4-hydroxyphenylethylen glycol (MHPG), were determined by high-performance liquid chromatography (HPLC) with electrochemical detection as described previously (Laorden et al, 2000a). Bilateral tissue samples of the PVN were dissected according to the technique of Palkovits (1973), weighed, placed in perchloric acid (0.1 M), homogenized, and centrifuged, and the supernatants were taken for analysis and filtered through 0.22-m GV filter (Millipore Corporation).…”