Methadone and valproate combination effect on acquisition and expression of morphine dependence and tolerance in male mice

Abstract Background and Objective: According to the issue of dependence and tolerance in addicted patients, the inefficiency of existing treatments and the new recommendation for drug combination therapy for diseases in modern pharmacology, the present study examined the effect of methadone and valproate combination on morphine dependence and tolerance. Materials and Methods: Ninety-eight male mice were divided into the following groups: saline, morphine, methadone, valproate, and three groups of valproate+methadone, i.e. 1 to 1, 2 to 1 and 1 to 2 ratios. Except for the saline group, the others received escalating dose of morphine for 8 consecutive days. In acquisition group, drugs were injected for 30 minutes before morphine administration. In expression group, the drugs were used only at 8th day (test day). Morphine tolerance was measured by tail immersion test and for dependence assessment, naloxone-induced withdrawal signs was evaluated. Results: Jumping behavior as a main sign of dependence in both acquisition and expression significantly reduced in methadone1+valproate2 treatment group. Also, acquisition and expression of tolerance significantly decreased in valproate and methadone1+valproate2 more than other groups. Conclusion: Our results show that methadone and valproate combination treatment could probably reduce tolerance and dependence more than single valproate or methadone treatments.