title: Spironolactone decreases the somatic signs of opiate withdrawal by blocking the mineralocorticoid receptors (MR).
abstract: Pharmacological evidence has accumulated showing that glucocorticoids and glucocorticoid receptor (GR) facilitate several responses to different drugs of abuse. Recent findings have attributed a prominent role to the mineralocorticoid receptor (MR) in modulating behavior during the addictive process. The purpose of this study was to investigate the effects of MR blockade on: brain stress system responses to naloxone-induced morphine withdrawal, the somatic signs of abstinence; the effects of morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), c-Fos expression and tyrosine hydroxylase (TH) phosphorylated at Ser31 levels in the nucleus tractus solitarius noradrenergic cell group (NTS-A2); and finally, hypothalamus-pituitary-adrenocortical (HPA) axis activity. The role of MR signaling was assessed with i.p. pretreatment with the MR antagonist, spironolactone. Rats were implanted with two morphine (or placebo) pellets. Six days later rats were pretreated with spironolactone or vehicle 30min before naloxone. The physical signs of abstinence, NA turnover, TH activation, c-Fos expression and the HPA axis activity were measured using HPLC, immunoblotting and RIA. Spironolactone attenuated the somatic signs of withdrawal that were seen after naloxone administration to chronic morphine treated animals. On the other hand, pretreatment with spironolactone resulted in no significant modification of the increased NA turnover, TH activation, c-Fos expression or HPA axis activity that occurred during morphine withdrawal. These results suggest that somatic signs of opiate withdrawal are modulated by MR signaling. However, blockade of MR did not significantly alter the brain stress system response to morphine withdrawal.
authors.affiliation: Group of Cellular and Molecular Pharmacology, University School of Medicine, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain. Electronic address: jnavarrozaragoza@um.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Navarro-Zaragoza
authors.affiliation: Group of Cellular and Molecular Pharmacology, University School of Medicine, 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, University School of Medicine, 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; D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009020:Morphine; D009270:Naloxone; D009292:Narcotic Antagonists; D009638:Norepinephrine / Q000378:metabolism; D009293:Opioid-Related Disorders / Q000150:complications* / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D000451:Mineralocorticoid Receptor Antagonists; D009292:Narcotic Antagonists; D016760:Proto-Oncogene Proteins c-fos; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D009270:Naloxone; D009020:Morphine; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine
keywords: Mineralocorticoid receptor; Morphine dependence; Noradrenergic activity; Opiate withdrawal; Spironolactone; Withdrawal signs