1. Protein kinase C phosphorylates the cAMP response element binding protein in the hypothalamic paraventricular nucleus during morphine withdrawal.
- Author
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Martín F, Mora L, Laorden M, and Milanés M
- Subjects
- Animals, Benzophenanthridines pharmacology, Corticotropin-Releasing Hormone metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Hypothalamo-Hypophyseal System drug effects, Hypothalamo-Hypophyseal System metabolism, MAP Kinase Kinase Kinases antagonists & inhibitors, MAP Kinase Kinase Kinases metabolism, Male, Mitogen-Activated Protein Kinase 3, Morphine Dependence enzymology, Morphine Dependence metabolism, Naloxone pharmacology, Naphthalenes pharmacology, Paraventricular Hypothalamic Nucleus enzymology, Phosphorylation drug effects, Pituitary-Adrenal System drug effects, Pituitary-Adrenal System metabolism, Protein Kinase C antagonists & inhibitors, Rats, Rats, Sprague-Dawley, Substance Withdrawal Syndrome enzymology, Cyclic AMP Response Element-Binding Protein metabolism, Morphine pharmacology, Paraventricular Hypothalamic Nucleus drug effects, Paraventricular Hypothalamic Nucleus metabolism, Protein Kinase C metabolism, Substance Withdrawal Syndrome metabolism
- Abstract
Background and Purpose: Exposure to drugs of abuse or stress results in adaptation in the brain involving changes in gene expression and transcription factors. Morphine withdrawal modulates gene expression through various second-messenger signal transduction systems. Here, we investigated changes in activation of the transcription factor, cAMP-response element binding protein (CREB), in the hypothalamic paraventricular nucleus (PVN) and the kinases that may mediate the morphine withdrawal-triggered activation of CREB and the response of the hypothalamic-pituitary-adrenocortical (HPA) axis after naloxone-induced morphine withdrawal., Experimental Approach: The effects of morphine dependence and withdrawal, phosphorylated CREB (pCREB), corticotrophin-releasing factor (CRF) expression in the PVN and HPA axis activity were measured using immunoblotting, immunohistochemistry and radioimmunoassay in controls and in morphine-dependent rats, withdrawn with naloxone and pretreated with vehicle, calphostin C, chelerythrine (inhibitors of protein kinase C (PKC) or SL-327 [inhibitor of extracellular signal regulated kinase (ERK) kinase]. In addition, changes in PKCα and PKCγ immunoreactivity were measured after 60 min of withdrawal., Key Results: In morphine-withdrawn rats, pCREB immunoreactivity was increased within CRF immunoreactive neurons in the PVN and plasma corticosterone levels were raised. SL-327, at doses that reduced the augmented pERK levels in the PVN, did not attenuate the rise in pCREB immunoreactivity or plasma corticosterone secretion. In contrast, PKC inhibition reduced the withdrawal-triggered rise in pCREB, pERK1/2 and corticosterone secretion., Conclusions and Implications: PKC mediated, in part, both CREB activation and the HPA response to morphine withdrawal. The ERK kinase/ERK pathway might not be necessary for either activation of CREB or HPA axis hyperactivity., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)
- Published
- 2011
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