Introduction: Chronic opiate exposure induces tolerance to opiate analgesic effects. Glutamate system is believed to play a major role in morphine induced tolerance. The inhibitory effects of magnesium sulfate and bupropion on this system are well-studied. The aim of this study was to evaluate the effects of magnesium sulfate and bupropion on the prevention of morphine induced tolerance in mice. Materials and Methods: Animals were divided into the nine groups which received drugs intraperitoneally for four consecutive days according to the following protocol: saline (10 ml/kg) + saline (10 ml/kg), morphine (50 mg/kg) + saline (10 ml/kg), morphine (50 mg/kg) + magnesium sulfate (20, 40 and 60 mg/kg), morphine (50 mg/kg) + bupropion (2, 4 and 8 mg/kg) and morphine (50 mg/kg) + magnesium sulfate (20 mg/kg) + bupropion (2 mg/kg). To evaluate the effects of mentioned drugs on morphine tolerance, a test dose of morphine (9 mg/kg) was administered on the fifth day in all groups. In the hot-plate test, thermal stimulation was measured at time intervals of 0, 15, 30, 45 and 60 minutes. Results: Administration of magnesium sulfate, bupropion and their combination before daily injection of morphine, significantly attenuated tolerance to morphine. Also, the highest tolerance reduction was observed at the 30th minute of the study (P<0.001). Conclusion: Magnesium sulfate and bupropion can be used to attenuate morphine induced tolerance. The possible mechanisms are antagonist behavior on N-methyl-D-aspartate (NMDA) receptor and inhibition of glutamate release, respectively.
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