Protein kinase C phosphorylates the cAMP response element binding protein in the hypothalamic paraventricular nucleus during morphine withdrawal.

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measured using immunoblotting, immunohistochemistry and radioimmunoassay in controls and in morphine-dependent rats, withdrawn with naloxone and pretreated with vehicle, calphostin C, chelerythrine (inhibitors of protein kinase C (PKC) or SL-327 [inhibitor of extracellular signal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In morphine-withdrawn rats, pCREB immunoreactivity was increased within CRF immunoreactive neurons in the PVN and plasma corticosterone levels were raised.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.

• Authors: F Martín, L Mora, Ml Laorden, Mv Milanés
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 163 Issue 4 Pg. 857-75 (Jun 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 21615389 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• Benzophenanthridines
• Cyclic AMP Response Element-Binding Protein
• Naphthalenes
• Naloxone
• Morphine
• Corticotropin-Releasing Hormone
• chelerythrine
• Protein Kinase C
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase 3
• MAP Kinase Kinase Kinases
• calphostin C

Topics

• Animals
• Benzophenanthridines (pharmacology)
• Corticotropin-Releasing Hormone (metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Hypothalamo-Hypophyseal System (drug effects, metabolism)
• MAP Kinase Kinase Kinases (antagonists & inhibitors, metabolism)
• Male
• Mitogen-Activated Protein Kinase 3
• Morphine (pharmacology)
• Morphine Dependence (enzymology, metabolism)
• Naloxone (pharmacology)
• Naphthalenes (pharmacology)
• Paraventricular Hypothalamic Nucleus (drug effects, enzymology, metabolism)
• Phosphorylation (drug effects)
• Pituitary-Adrenal System (drug effects, metabolism)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Rats
• Rats, Sprague-Dawley
• Substance Withdrawal Syndrome (enzymology, metabolism)