title: Glucocorticoid receptor but not mineralocorticoid receptor mediates the activation of ERK pathway and CREB during morphine withdrawal.
abstract: Recent research suggests that glucocorticoids are involved in the development of addiction to drugs of abuse. They share this role with dopamine (DA), and with different signalling pathways and/or transcription factors such as extracellular-signal regulated kinases (ERK) and cAMP response element binding protein (CREB). However, the relation between them is not completely elucidated. In this report, we further characterize the role of glucocorticoid and mineralocorticoid receptor (GR and MR) signalling in DA turnover at the Nacc, and in opiate withdrawal-induced tyrosine hydroxylase (TH) expression, ERK and CREB phosphorylation (activation) in the nucleus of tractus solitarius (NTS-A2). The role of GR and MR signalling was assessed with the selective GR antagonist, mifepristone or the MR antagonist, spironolactone (i.p.). Rats were implanted two morphine (or placebo) pellets. Six days later rats were pretreated with mifepristone, spironolactone or vehicle 30 min before naloxone, and DA turnover, TH expression, ERK and CREB phosphorylation, were measured using HPLC and immunoblotting. Glucocorticoid receptor blockade attenuated ERK and CREB phosphorylation and the TH expression induced by morphine withdrawal. In contrast, no changes were seen after MR blockade. Finally, GR and MR blockade did not alter the morphine withdrawal-induced increase seen both in DA turnover and DA metabolite production, in the NAcc. These results show that not only ERK and CREB phosphorylation but also TH expression in the NTS is modulated by GR signalling. The present results suggest that GR is a therapeutic target to improve aversive events associated with opiate withdrawal.
authors.affiliation: Group of Cellular and Molecular Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain.|Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Navarro-Zaragoza
authors.affiliation: Group of Cellular and Molecular Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain.|Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Laorden
authors.affiliation: Group of Cellular and Molecular Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain.|Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Milanés
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013148:Spironolactone / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D017362:Cyclic AMP Response Element-Binding Protein; D006727:Hormone Antagonists; D000451:Mineralocorticoid Receptor Antagonists; C542344:NR3C1 protein, rat; D009292:Narcotic Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D015735:Mifepristone; D009270:Naloxone; D009020:Morphine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: CREB phosphorylation; DA turnover; ERK pathway; NTS-A2 noradrenergic cell group; glucocorticoid receptor; mifepristone; mineralocorticoid receptor; morphine withdrawal; nucleus accumbens; spironolactone