Attenuation of Morphine-Induced Tolerance and Dependency by Pretreatment with Magnesium Sulfate and Amitriptyline in Male Mice

Clinical use of Morphine in pain management is a controversial issue and long-term exposure to opiates induces physical dependency and tolerance. The aim of this study was to evaluate the attenuation effects of Magnesium sulfate and Amitriptyline on the development of Morphine-induced dependency and tolerance. In this study different groups of mice were received saline (10 mL/kg,ip), Morphine (50 mg/kg,ip), Magnesium sulfate (20, 40 and 60 mg/kg,ip), Amitriptyline (5, 10 and 15 or 20 mg/kg,ip), or combination of Magnesium sulfate (20 mg/kg,ip) and Amitriptyline (5 mg/kg,ip) once a day for 4 and 10 continues days, respectively for investigation of the effects of Magnesium sulfate and Amitriptyline on the prevention of dependency and tolerance. Tolerance was assessed by administration of Morphine (9 mg/kg,ip) and using hot plate test on eleventh day. Withdrawal symptoms were assessed in fifth day by administration of naloxone (4 mg/kg,ip), 2 hrs after last dose of Morphine during 30 minutes for each animal. It was found that pretreatment with Magnesium sulfate or Amitriptyline decreased the development of tolerance to the antinociceptive action of Morphine and also reduced naloxone-precipitated withdrawal jumps and standing on feet. Additionally, pretreatment by co-administration of Magnesium sulfate and Amitriptyline, before morphine administration, decreased the dependency and tolerance more significantly. From these results it could be concluded that pretreatment of Magnesium sulfate via blocking the N-methyl-D-Aspartate receptor-operated calcium channel and Amitriptyline by Glutamate transporter activation property alone or in combination could prevent the development of Morphine-induced dependency and tolerance.