title: Cardiac adverse effects of naloxone-precipitated morphine withdrawal on right ventricle: role of corticotropin-releasing factor (CRF) 1 receptor.
abstract: Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic-pituitary-adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts.
authors.affiliation: Department of Pharmacology, University of Murcia, Murcia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Navarro-Zaragoza
authors.affiliation: Department of Pharmacology, University of Murcia, Murcia, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Martínez-Laorden
authors.affiliation: Department of Pharmacology, University of Murcia, Murcia, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Mora
authors.affiliation: Department of Pharmacology, University of Murcia, Murcia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Hidalgo
authors.affiliation: Department of Pharmacology, University of Murcia, Murcia, Spain.
authors.forename: M V
authors.initials: MV
authors.lastname: Milanés
authors.affiliation: Department of Pharmacology, University of Murcia, Murcia, Spain. Electronic address: laorden@um.es.
authors.forename: M L
authors.initials: ML
authors.lastname: Laorden
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009021:Morphine Dependence / Q000188:drug therapy* / Q000503:physiopathology; D009270:Naloxone / Q000009:adverse effects / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000517:prevention & control*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000209:etiology / Q000517:prevention & control; D015430:Weight Gain / Q000187:drug effects; D000099052:CRF Receptor, Type 1
chemical_list: D002316:Cardiotonic Agents; D009292:Narcotic Antagonists; D018019:Receptors, Corticotropin-Releasing Hormone; D009270:Naloxone; D000099052:CRF Receptor, Type 1; D014446:Tyrosine 3-Monooxygenase
keywords: Extracellular signal-regulated kinase; Hypothalamus–pituitary–adrenocortical axis; Morphine withdrawal; Noradrenaline turnover; Right ventricle; Tyrosine hydroxylase