Differential involvement of 3', 5'-cyclic adenosine monophosphate-dependent protein kinase in regulation of Fos and tyrosine hydroxylase expression in the heart after naloxone induced morphine withdrawal.
We previously demonstrated that morphine withdrawal induced hyperactivity of the heart by the activation of noradrenergic pathways innervating the left and right ventricle, as evaluated by noradrenaline (NA) turnover and Fos expression. We investigated whether cAMP-dependent protein kinase (PKA) plays a role in this process by estimating changes in PKA immunoreactivity and the influence of inhibitor of PKA on Fos protein expression, tyrosine hydroxylase (TH) immunoreactivity levels and NA turnover in the left and right ventricle. Dependence on morphine was induced by a 7-day s.c. implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (5 mg/kg). When opioid withdrawal was precipitated, an increase in PKA immunoreactivity and phospho-CREB (cyclic AMP response element protein) levels were observed in the heart. Moreover, morphine withdrawal induces Fos expression, an enhancement of NA turnover and an increase in the total TH levels. When the selective PKA inhibitor HA-1004 was infused, concomitantly with morphine pellets, it diminished the increase in NA turnover and the total TH levels observed in morphine-withdrawn rats. However, this inhibitor neither modifies the morphine withdrawal induced Fos expression nor the increase of nonphosphorylated TH levels. The present findings indicate that an up-regulated PKA-dependent transduction pathway might contribute to the activation of the cardiac catecholaminergic neurons in response to morphine withdrawal and suggest that Fos is not a target of PKA at heart levels.
Almela
Pilar
P
Equip of Cellular and Molecular Pharmacology, University School of Medicine, Murcia, Spain.
Cerezo
Manuela
M
González-Cuello
A
A
Milanés
M Victoria
MV
Laorden
M Luisa
ML
D000818:Animals; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004343:Drug Implants; D007120:Immunochemistry; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000633:toxicity; D009206:Myocardium / Q000378:metabolism*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage / Q000633:toxicity; D009638:Norepinephrine / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D004343:Drug Implants; D007546:Isoquinolines; D009292:Narcotic Antagonists; D009294:Narcotics; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D013449:Sulfonamides; D009270:Naloxone; D009020:Morphine; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D014446:Tyrosine 3-Monooxygenase; D017868:Cyclic AMP-Dependent Protein Kinases; D009638:Norepinephrine