title: Simvastatin prevents morphine antinociceptive tolerance and withdrawal symptoms in rats.
abstract: OBJECTIVE
  Long-term exposure to opiates induces tolerance to the analgesic effect and dependence. In recent years, several studies have been conducted to find agents that can prevent the development of these two phenomena. The aim of the present study is to evaluate the effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on morphine-induced tolerance and withdrawal symptoms.
  
  
  METHODS
  Groups of male rats received daily morphine [for induction of tolerance (10 mg/kg) and for induction of dependence (additive doses: 5 mg/kg/12 h, 10 mg/kg/12 h, 15 mg/kg/12 h, 20 mg/kg/12 h, and 25 mg/kg/12 h)] in combination with propylene glycol or simvastatin [5 mg/kg, per os (p.o.), 10 mg/kg, p.o., and 20 mg/kg, p.o.]. Next, the nociception was assessed by the plantar test apparatus. The latency was recorded when the animal responded to the light stimulus. The animals received additional doses of morphine for 9 days in order to induce dependency. One hour after the last dose of the morphine injection, naloxone was administered and withdrawal symptoms were recorded for 1 hour.
  
  
  RESULTS
  The results of the present study showed that chronic morphine administration induced tolerance to the analgesic effect for 19 days, whereas simvastatin (20 mg/kg, p.o.) delayed the day of the established tolerance by 5 days. The administration of simvastatin also prevented the morphine-induced shift to the right of the 50% effective dose (ED50) in the dose-response curve. Furthermore, the results showed that simvastatin decreased the total withdrawal score significantly.
  
  
  CONCLUSIONS
  We found that simvastatin attenuated morphine-induced tolerance and withdrawal symptoms.
authors.affiliation: Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Ghasemi
authors.affiliation: Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Moradi
authors.affiliation: Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran; Department of Physiology and Pharmacology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
authors.forename: Esmael
authors.initials: E
authors.lastname: Izadpanah
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
authors.forename: Mohammad Raman
authors.initials: MR
authors.lastname: Moloudi
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
authors.forename: Katayoun
authors.initials: K
authors.lastname: Hassanzadeh
authors.affiliation: Department of Bioscience and Biotechnology, University of Kurdistan, Sanandaj, Iran.
authors.forename: Arman
authors.initials: A
authors.lastname: Rahimmi
authors.affiliation: Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran; Department of Physiology and Pharmacology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran. Electronic address: kambizhassanzadeh@gmail.com.
authors.forename: Kambiz
authors.initials: K
authors.lastname: Hassanzadeh
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D008297:Male; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology*; D009021:Morphine Dependence / Q000188:drug therapy*; D009270:Naloxone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000008:administration & dosage*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009292:Narcotic Antagonists; D009270:Naloxone; D009020:Morphine; D019821:Simvastatin
keywords: morphine; simvastatin; tolerance; withdrawal symptoms