title: Involvement of 3',5'-cyclic adenosine monophosphate-dependent protein kinase in regulation of Fos expression and tyrosine hydroxylase levels during morphine withdrawal in the hypothalamic paraventricular nucleus and medulla oblongata catecholaminergic cell groups.
abstract: Morphine withdrawal stimulates the hypothalamic-pituitary-adrenocortical axis activity by activation of nucleus tractus solitarius (NTS)/ventrolateral medulla (VLM) noradrenergic pathways innervating the hypothalamic paraventricular nucleus (PVN). We investigated whether cAMP-dependent protein kinase (PKA) plays a role in this process by estimating changes in PKA immunoreactivity and the influence of inhibition of PKA on Fos protein expression and tyrosine hydroxylase (TH) immunoreactivity levels in the PVN and NTS/VLM during morphine withdrawal. 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 s.c.). When opioid withdrawal was precipitated, an increase in PKA immunoreactivity levels was observed 90 min after naloxone administration in the PVN and NTS/VLM areas. Morphine withdrawal induced expression of Fos in the PVN and NTS/VLM, indicating an activation of neurones in those nuclei. TH immunoreactivity in NTS/VLM was increased 90 min after induction of morphine withdrawal, whereas there was a decrease in TH levels in the PVN at the same time point. When the selective PKA inhibitor HA-1004 was infused it greatly diminished the Fos expression observed in morphine-withdrawn rats. Furthermore, the changes in TH immunoreactivity were significantly modified by infusion of HA-1004. The present findings suggest that an up-regulated PKA-dependent transduction pathway might contribute to the activation of the hypothalamic-pituitary-adrenocortical axis in response to morphine withdrawal.
authors.affiliation: Equip of Cellular and Molecular Pharmacology, University School of Medicine, Murcia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Benavides
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Laorden
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Milanés
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002395:Catecholamines / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D004343:Drug Implants; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism*; D009020:Morphine / Q000009:adverse effects; D009021:Morphine Dependence / Q000378:metabolism; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000009:adverse effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017552:Solitary Nucleus / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
chemical_list: D002395:Catecholamines; D004343:Drug Implants; D007546:Isoquinolines; D009292:Narcotic Antagonists; D009294:Narcotics; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D013449:Sulfonamides; D009020:Morphine; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D014446:Tyrosine 3-Monooxygenase; D017868:Cyclic AMP-Dependent Protein Kinases