title: Attenuation of morphine-induced dependence and tolerance by ceftriaxone and amitriptyline in mice.
abstract: BACKGROUND
  Tolerance to and dependence on the analgesic effect of opioids is a pharmacological phenomenon that occurs after their prolonged administration.
  
  
  OBJECTIVE
  The aim of this study was to evaluate the protective effects of ceftriaxone and amitriptyline on the development of morphine-induced tolerance and dependence.
  
  
  METHODS
  In this study, 18 groups (9 groups each for tolerance and dependency tests) of mice (n = 8) received saline [10 mL/kg, intraperitoneally (i.p.)], morphine (50 mg/kg, i.p.), ceftriaxone (50 mg/kg, i.p., 100 mg/kg, i.p., and 200 mg/kg, i.p.), amitriptyline (5 mg/kg, i.p., 10 mg/kg, i.p., and 15 mg/kg, i.p.), or a combination of ceftriaxone (50 mg/kg, i.p.) and amitriptyline (5 mg/kg, i.p.) once per day for 4 days for investigation and comparison of the effects of ceftriaxone and amitriptyline on the prevention of dependency and tolerance to morphine. Tolerance was assessed with administration of morphine (9 mg/kg, i.p.) and using the hot plate test on the 5(th) day. In dependency tests, withdrawal symptoms were assessed on the 4(th) day for each animal 30 minutes after the administration of naloxone (4 mg/kg, i.p.; 2 hours after the last dose of morphine).
  
  
  RESULTS
  It was found that treatment with ceftriaxone or amitriptyline attenuated the development of tolerance to the antinociceptive effect of morphine and also reduced naloxone-precipitated withdrawal jumping and standing on feet. Furthermore, coadministration of ceftriaxone and amitriptyline at low doses (50 mg/kg, i.p. and 5 mg/kg, i.p., respectively) prior to morphine injection also decreased both morphine-induced tolerance and dependence.
  
  
  CONCLUSIONS
  Results indicate that the treatment with ceftriaxone and amitriptyline, alone or in combination, could attenuate the development of morphine-induced tolerance and dependence.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Bohlul
authors.initials: B
authors.lastname: Habibi-Asl
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Haleh
authors.initials: H
authors.lastname: Vaez
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Moslem
authors.initials: M
authors.lastname: Najafi
authors.affiliation: Student Research Committee, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Bidaghi
authors.affiliation: Student Research Committee, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center for Pharmaceutical Nanotechnology and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address: Ghanbarzadehs@tbzmed.ac.ir.
authors.forename: Saeed
authors.initials: S
authors.lastname: Ghanbarzadeh
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D002443:Ceftriaxone / Q000494:pharmacology*; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D009020:Morphine / Q000009:adverse effects*; D009021:Morphine Dependence / Q000517:prevention & control*
chemical_list: D000639:Amitriptyline; D002443:Ceftriaxone; D009020:Morphine
keywords: amitriptyline; ceftriaxone; dependency; morphine; tolerance; β-lactam antibiotic