title: Prevention of morphine dependence and tolerance by Nepeta menthoides was accompanied by attenuation of Nitric oxide overproduction in male mice.
abstract: BACKGROUND
  Repeated administration of morphine for chronic pain leads to dependence and tolerance that limits clinical usage. Nepeta menthoides is commonly known as Iranian Ustukhuddoos and are administered in traditional medicine for gastrodynia, bone pain, blood depurative and restlessness.
  
  
  OBJECTIVE
  To investigate the effects of Nepeta menthoides on expression and acquisition of morphine dependence and tolerance in mice with regard to oxidative stress.
  
  
  METHODS
  Morphine dependence in mice was developed by administration of gradually increasing doses of morphine twice daily for 7 consecutive days. In experimental groups, administration of Nepeta menthoides (200 and 400mg/kg), methadone and their combination were performed 60min prior to each morphine injection (for acquisition) or the last injection of morphine on test day (for expression). Morphine tolerance was measured by the tail-immersion test before and after the administration of a single dose of morphine (100mg/kg; i.p.) on the test day (8th day). Morphine dependence was also evaluated by counting the number of jumps after the injection of naloxone (5mg/kg; i.p.).
  
  
  RESULTS
  Nepeta menthoides, similar to methadone, significantly prevented the development (but not the expression) of morphine dependence, tolerance, and potentiated morphine antinociception and also reduced (23.23±1.15) Nitric oxide (NO) overproduction (35.23±3.36) (in compared with naloxone group (6.3±0.52)). However, single and repeated application of the extract could not change high single-dose morphine analgesia.
  
  
  CONCLUSIONS
  It appears that Nepeta menthoides and methadone prevented morphine dependence and tolerance, partly through inhibition of the NO overproduction.
authors.affiliation: Neurophysiology Research Center, Shahed University, 1417953836 Tehran, Iran; Department of Physiology, School of Medicine, Shahed University, 3319118651 Tehran, Iran. Electronic address: batrahmati@yahoo.com.
authors.forename: Batool
authors.initials: B
authors.lastname: Rahmati
authors.affiliation: Department of Physiology, School of Medicine, Shahed University, 3319118651 Tehran, Iran. Electronic address: ahmadbeik48@yahoo.com.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Beik
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology; D008297:Male; D008691:Methadone / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009021:Morphine Dependence / Q000378:metabolism* / Q000517:prevention & control*; D027521:Nepeta; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation
chemical_list: D010936:Plant Extracts; D009569:Nitric Oxide; D008691:Methadone
keywords: Malondialdehyde; Methadone HCl (PubChem CID:14184); Morphine antinociception; Morphine dependence and tolerance; Morphine sulfate (PubChem CID: 5464280); Naloxone HCl (PubChem CID: 5464092); Nepeta menthoides; Nitric Oxide; Tail immersion test