Activation of the ERK signalling pathway contributes to the adaptive changes in rat hearts during naloxone-induced morphine withdrawal.
OBJECTIVE
We have previously demonstrated that morphine withdrawal induced hyperactivity of the heart by activation of noradrenergic pathways innervating the left and right ventricle, as evaluated by noradrenaline turnover and c-Fos expression. The extracellular signal-regulated kinase (ERK) has been implicated in drug addiction, but its role in activation of the heart during morphine dependence remains poorly understood. Here, we have looked for activation of ERK during morphine withdrawal and if this activation induced gene expression.


METHODS
Dependence on morphine was induced by s.c. implantation of morphine pellets for 7 days. Morphine withdrawal was precipitated on day 8 by injection of naloxone (2 mg kg(-1), s.c.). ERK1/2, their phosphorylated forms and c-Fos were measured by western blotting and immunohistochemistry of cardiac tissue.


RESULTS
Naloxone-induced morphine withdrawal activated ERK1/2 and increased c-Fos expression in cardiac tissues. c-Fos expression was blocked by SL327, a drug that prevents ERK activation.


CONCLUSIONS
These results indicate that signalling through the ERKs is necessary for morphine withdrawal-induced hyperactivity of the heart and suggest that this pathway may also be involved in activation of immediate-early genes in both cytosolic and nuclear effector mechanisms that have the potential to bring about long-term changes in the heart.
Almela
P
P
Department of Pharmacology, University School of Medicine, Murcia, Spain.
Milanés
M V
MV
Laorden
M L
ML
D000607:Aminoacetonitrile / Q000031:analogs & derivatives; D000818:Animals; D015153:Blotting, Western; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000009:adverse effects*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000503:physiopathology
D009292:Narcotic Antagonists; D009294:Narcotics; C424127:SL 327; D009270:Naloxone; D000607:Aminoacetonitrile; D009020:Morphine; D048049:Extracellular Signal-Regulated MAP Kinases