title: Glucocorticoid receptors participate in the opiate withdrawal-induced stimulation of rats NTS noradrenergic activity and in the somatic signs of morphine withdrawal.
abstract: OBJECTIVE
  Recent evidence suggests that glucocorticoid receptor (GR) is a major molecular substrate of addictive properties of drugs of abuse. Hence, we performed a series of experiments to further characterize the role of GR signalling in opiate withdrawal-induced physical signs of dependence, enhanced noradrenaline (NA) turnover in the hypothalamic paraventricular nucleus (PVN) and tyrosine hydroxylase (TH) phosphorylation (activation) as well as GR expression in the nucleus of the solitary tract noradrenergic cell group (NTS-A₂).
  
  
  METHODS
  The role of GR signalling was assessed by i.p. pretreatment of the selective GR antagonist, mifepristone. Rats were implanted with two morphine (or placebo) pellets. Six days later, rats were pretreated with mifepristone or vehicle 30 min before naloxone and physical signs of abstinence, NA turnover, TH activation, GR expression and the hypothalamus-pituitary-adrenocortical axis activity were measured using HPLC, immunoblotting and RIA.
  
  
  RESULTS
  Mifepristone alleviated the somatic signs of naloxone-induced opiate withdrawal. Mifepristone attenuated the increase in the NA metabolite, 3-methoxy-4-hydroxyphenylethylen glycol (MHPG), in the PVN, and the enhanced NA turnover observed in morphine-withdrawn rats. Mifepristone antagonized the TH phosphorylation at Ser³¹ and the expression of c-Fos expression induced by morphine withdrawal. Finally, naloxone-precipitated morphine withdrawal induced up-regulation of GR in the NTS.
  
  
  CONCLUSIONS
  These results suggest that the physical signs of opiate withdrawal, TH activation and stimulation of noradrenergic pathways innervating the PVN are modulated by GR signalling. Overall, the present data suggest that drugs targeting the GR may ameliorate stress and aversive effects associated with opiate withdrawal.
authors.affiliation: Group of Cellular and Molecular Pharmacology, University School of Medicine, Murcia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Navarro-Zaragoza
authors.forename: Juana M
authors.initials: JM
authors.lastname: Hidalgo
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Laorden
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Milanés
mesh_terms: D000818:Animals; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009021:Morphine Dependence / Q000503:physiopathology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000502:physiology*; D017552:Solitary Nucleus / Q000503:physiopathology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D014446:Tyrosine 3-Monooxygenase / Q000502:physiology
chemical_list: D006727:Hormone Antagonists; D009292:Narcotic Antagonists; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D009270:Naloxone; D014446:Tyrosine 3-Monooxygenase