Spironolactone decreases the somatic signs of opiate withdrawal by blocking the mineralocorticoid receptors (MR)

• Published in: Toxicology (Amsterdam) Vol. 326; pp. 36 - 43
• Main Authors: Navarro-Zaragoza, Javier, Laorden, M.Luisa, Milanés, M.Victoria
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 04-12-2014
• Subjects: Activation; Analgesics, Opioid; Animals; Blocking; Brain; Disease Models, Animal; Emergency; Enzyme Activation; Glucocorticoids; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - metabolism; Hypothalamus - drug effects; Hypothalamus - metabolism; Male; Mineralocorticoid receptor; Mineralocorticoid Receptor Antagonists - pharmacology; Morphine; Morphine dependence; Naloxone; Narcotic Antagonists; Noradrenergic activity; Norepinephrine - metabolism; Nuclei; Opiate withdrawal; Opioid-Related Disorders - complications; Opioid-Related Disorders - metabolism; Paraventricular Hypothalamic Nucleus - drug effects; Paraventricular Hypothalamic Nucleus - metabolism; Phosphorylation; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - metabolism; Pretreatment; Proto-Oncogene Proteins c-fos - metabolism; Rats, Sprague-Dawley; Receptors; Receptors, Mineralocorticoid - drug effects; Receptors, Mineralocorticoid - metabolism; Signal Transduction - drug effects; Spironolactone; Spironolactone - pharmacology; Substance Withdrawal Syndrome - etiology; Substance Withdrawal Syndrome - metabolism; Substance Withdrawal Syndrome - prevention & control; Tyrosine 3-Monooxygenase - metabolism; Withdrawal signs; nucleus of the solitary tract-A 2 noradrenergic cell group; MR; hypothalamus–pituitary–adrenocortical; Opiate withdrawal; Morphine dependence; PVN; Noradrenergic activity; mineralocorticoid receptor; hypothalamic paraventricular nucleus; tyrosine hydroxylase; TH; Spironolactone; Withdrawal signs; NTS-A 2; HPA; NTS-A2; Mineralocorticoid receptor
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2014.10.002

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 30 min 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.