title: Cross-talk between protein kinase A and mitogen-activated protein kinases signalling in the adaptive changes observed during morphine withdrawal in the heart.
abstract: Our previous studies have shown that morphine withdrawal induced an increase in the expression of protein kinase (PK) A and mitogen-activated extracellular kinase (MAPK) pathways in the heart during morphine withdrawal. The purpose of the present study was to evaluate the interaction between PKA and extracellular signal-regulated kinase (ERK) signaling pathways mediating the cardiac adaptive changes observed after naloxone administration to morphine-dependent rats. Dependence on morphine was induced by a 7-day subcutaneous implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (2 mg/kg). ERK1/2 and tyrosine hydroxylase (TH) phosphorylation was determined by quantitative blot immunolabeling using phosphorylation state-specific antibodies. Naloxone-induced morphine withdrawal activates ERK1/2 and phosphorylates TH at Ser31 in the right and left ventricle, with an increase in the mean arterial blood pressure and heart rate. When N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004), a PKA inhibitor, was infused, concomitantly with morphine, it diminished the expression of ERK1/2. In contrast, the infusion of calphostin C (a PKC inhibitor) did not modify the morphine withdrawal-induced activation of ERK1/2. The ability of morphine withdrawal to activate ERK that phosphorylates TH at Ser31 was reduced by HA-1004. The present findings demonstrate that the enhancement of ERK1/2 expression and the phosphorylation state of TH at Ser31 during morphine withdrawal are dependent on PKA and suggest cross-talk between PKA and ERK1/2 transduction pathway mediating morphine withdrawal-induced activation (phosphorylation) of TH.
authors: Department of Pharmacology, Faculty of Medicine, University of Murcia, Spain.
authors: P
authors: P
authors: Almela
authors: N M
authors: NM
authors: Atucha
authors: M V
authors: MV
authors: Milanés
authors: M L
authors: ML
authors: Laorden
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D015153:Blotting, Western; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D013449:Sulfonamides / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000502:physiology; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009281:Naphthalenes; D009292:Narcotic Antagonists; C424127:SL 327; D013449:Sulfonamides; D009270:Naloxone; D000607:Aminoacetonitrile; D009020:Morphine; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D014446:Tyrosine 3-Monooxygenase; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C058819:calphostin C