Morphine withdrawal-induced c-fos expression in the heart: a peripheral mechanism.
We previously demonstrated that hyperactivity of cardiac noradrenergic pathways observed during morphine withdrawal is mediated by peripheral mechanisms. In the present study, naloxone methiodide (quaternary derivative of naloxone that does not cross the blood-brain barrier) and naloxone were administered to morphine-dependent rats and Fos immunostaining was used as a reflection of neuronal activity. Dependence on morphine was induced by 7-day chronic subcutaneous (s.c.) implantation of six morphine pellets (75 mg). Morphine withdrawal was precipitated by administration of naloxone methiodide (5 mg/kg, s.c.) or naloxone (5 mg/kg, s.c.) on day 8. Using immunohistochemical staining of Fos, present results indicate that the administration of naloxone methiodide or naloxone to morphine-dependent rats induced marked Fos immunoreactivity within the cardiomyocyte nuclei. Moreover, Western blot analysis revealed a peak expression of c-fos in the right and left ventricles after naloxone methiodide- or naloxone-precipitated withdrawal. In addition, in the hypothalamic paraventricular nucleus (PVN), Fos expression was increased after naloxone-but not after naloxone methiodide-administration to morphine-dependent rats. These results suggest that the activation of c-fos expression observed during morphine withdrawal in the heart is due to intrinsic mechanisms outside the central nervous system (CNS).
González-Cuello
Ana
A
Department of Cellular and Molecular Pharmacology, University School of Medicine, Murcia, Spain.
Milanés
M Victoria
MV
Castells
M Teresa
MT
Laorden
M Luisa
ML
D000818:Animals; D015153:Blotting, Western; D016762:Genes, fos / Q000235:genetics*; D006321:Heart / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009206:Myocardium / Q000378:metabolism*; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000009:adverse effects*; D009434:Neural Pathways / Q000187:drug effects; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D017933:Peripheral Nervous System / Q000187:drug effects*; D000644:Quaternary Ammonium Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000503:physiopathology*
D009292:Narcotic Antagonists; D009294:Narcotics; D000644:Quaternary Ammonium Compounds; D009270:Naloxone; C041269:N-methylnaloxone; D009020:Morphine