title: Attenuation of morphine tolerance and dependence by thymoquinone in mice.
abstract: OBJECTIVE
  Dependence and tolerance are major restricting factors in the clinical use of opioid analgesics. In the present study, the effects of thymoquinone, the major constituent of Nigella sativa seeds, on morphine dependence and tolerance were investigated in mice.
  
  
  METHODS
  Male adult NMRI mice were made tolerant and dependent by repeated injections of morphine (50, 50, and 75 mg/kg, i.p. on 9 a.m., 1 p.m., and 5 p.m., respectively) during a 3-day administration schedule. The hot-plate test was used to assess tolerance to the analgesic effects of morphine. Naloxone (2 mg/kg, i.p.) was injected to precipitate withdrawal syndrome in order to assess the morphine dependence. To evaluate the effects of thymoquinone on tolerance and dependence to morphine, different single or repeated doses of thymoquinone were administered in mice. Rotarod was used to assess the motor coordination.
  
  
  RESULTS
  Administration of single or repeated doses of thymoquinone (20 and 40 mg/kg, i.p.) significantly decreased the number of jumps in morphine dependent animals. Repeated administration of thymoquinone (20 and 40 mg/kg, for 3 days) and also single injection of thymoquinone (40 mg/kg, on the fourth day) attenuated tolerance to the analgesic effect of morphine. None of the thymoquinone doses (10, 20, and 40 mg/kg) produced any antinociceptive effects on their own. Motor coordination of animals was impaired by the high dose of thymoquinone (40 mg/kg).
  
  
  CONCLUSIONS
  Based on these results, it can be concluded that thymoquinone prevents the development of tolerance and dependence to morphine.
authors.affiliation: Pharmaceutical Research Center, Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Hosseinzadeh
authors.affiliation: Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Siavash
authors.initials: S
authors.lastname: Parvardeh
authors.affiliation: Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Masoudi
authors.affiliation: Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Moghimi
authors.affiliation: Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Mahboobifard
keywords: Dependence; Morphine; Nigella sativa; Thymoquinone; Tolerance; pain