Characterization of the signal transduction pathways mediating morphine withdrawal-stimulated c-fos expression in hypothalamic nuclei.
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 Ca2+ entry through L-type Ca2+ 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at its catalytic domain) with morphine did not affect the increase in Fos expression observed in nuclei from morphine withdrawn rats.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(HA-1004), was infused it greatly diminished the increased Fos production observed in morphine-withdrawn rats.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 Ca2+ 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significantly inhibited the enhancement of Fos induction in the paraventricular and supraoptic nuclei from morphine-withdrawn animals.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 Ca2+ system might contribute to the activation of Fos. The present findings suggest that protein kinase A and Ca2+ influx through L-type Ca2+ channels might contribute to the activation of neuroendocrine cells in the paraventricular and supraoptic nuclei.
Martínez
P J
PJ
Department of Pharmacology, Faculty of Medicine, Campus de Espinardo, 30100, Murcia, Spain.
Laorden
M L
ML
Cerezo
M
M
Martínez-Piñero
M G
MG
Milanés
M V
MV
D000818:Animals; D007025:Anterior Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000008:administration & dosage; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism; D013495:Supraoptic Nucleus / Q000187:drug effects / Q000378:metabolism
D020746:Calcium Channels, L-Type; D016760:Proto-Oncogene Proteins c-fos; D009270:Naloxone; D009020:Morphine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D002118:Calcium