Characterization of the signal transduction pathways mediating morphine withdrawal-stimulated c- fos expression in hypothalamic nuclei

• Published in: European journal of pharmacology 2001-10, Vol.430 (1), p.59-68
• Main Authors: Martı́nez, Pedro J, Laorden, M.Luisa, Cerezo, Manuela, Martı́nez-Piñero, M.Gloria, Milanés, M.Victoria
• Format: Article
• Language: English
• Subjects: Animals; Anterior Hypothalamic Nucleus - drug effects; Anterior Hypothalamic Nucleus - metabolism; Biological and medical sciences; c- fos; Ca 2+ channel; Calcium - metabolism; Calcium Channels, L-Type - drug effects; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Fundamental and applied biological sciences. Psychology; Hypothalamo-Hypophyseal System - drug effects; Male; Microbiology; Morphine - adverse effects; Morphine withdrawal; Naloxone - administration & dosage; Paraventricular Hypothalamic Nucleus - drug effects; Paraventricular Hypothalamic Nucleus - metabolism; Paraventricular nucleus; Pituitary-Adrenal System - drug effects; Protein kinase A; Protein kinase C; Protein Kinase C - antagonists & inhibitors; Proto-Oncogene Proteins c-fos - analysis; Proto-Oncogene Proteins c-fos - biosynthesis; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; Substance Withdrawal Syndrome - metabolism; Supraoptic nucleus; Supraoptic Nucleus - drug effects; Supraoptic Nucleus - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(01)01356-5

The transcription factor, Fos, is considered as a functional marker of activated neurons. We have shown previously that acute administration of morphine induces the expression of Fos in hypothalamic nuclei associated with control of the hypothalamus-pituitary-adrenocortex axis, such as the paraventricular nucleus and the supraoptic nucleus. In the current study, we examined the role of protein kinase A, protein kinase C and Ca 2+ entry through L-type Ca 2+ channels in naloxone-precipitated Fos expression in the paraventricular and supraoptic nuclei. After 7 days of morphine treatment, we did not observe any modification in Fos production. However, when opioid withdrawal was precipitated with naloxone a dramatic increase in Fos immunoreactivity was observed in the parvocellular division of the paraventricular nucleus and in the supraoptic nucleus. Chronic co-administration of chelerythrine (a selective protein kinase C inhibitor acting at its catalytic domain) with morphine did not affect the increase in Fos expression observed in nuclei from morphine withdrawn rats. In addition, infusion of calphostin C (another protein kinase C inhibitor, which interacts with its regulatory domain) did not modify the morphine withdrawal-induced expression of Fos. In contrast, when the selective protein kinase A inhibitor, N-(2′guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004), was infused it greatly diminished the increased Fos production observed in morphine-withdrawn rats. Furthermore, chronic infusion of the selective L-type Ca 2+ channel antagonist, nimodipine, significantly inhibited the enhancement of Fos induction in the paraventricular and supraoptic nuclei from morphine-withdrawn animals. Taken together, these data might indicate that protein kinase A activity is necessary for the expression of Fos during morphine withdrawal and that an up-regulated Ca 2+ system might contribute to the activation of Fos. The present findings suggest that protein kinase A and Ca 2+ influx through L-type Ca 2+ channels might contribute to the activation of neuroendocrine cells in the paraventricular and supraoptic nuclei.