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

Background and Objective: Today, opioids are used to control and relieve acute and chronic pain. However, the incidence of both tolerance and dependence phenomena for these drugs is a major problem. So, in this study, the combination effect of haloperidol and methadone on the acquisition and expression of morphine dependence and tolerance was examined.    Materials and Methods: Ninety-eight mice were randomly divided into groups of acquisition and expression. Each group was divided into seven sub-groups, saline, morphine, methadone, haloperidol, haloperidol + methadone, methadone + haloperidol ratio of 2 to 1, methadone + haloperidol ratio of 1 to 2. All groups were addicted with gradually increasing doses of morphine for 7 consecutive days. All drugs in the acquisition group were injected 30 minutes before morphine injected for 7 days and in the expression group 30 minutes before morphine injected in the eight day (test day). Morphine tolerance was measured by tail immersion test for 30 minutes before and after administration of morphine in test day. To assess dependence, mice were administered with naloxone and withdrawal behaviors were observed for 30 minutes. Results: Chronic morphine injections induced tolerance and dependence in mice. Percentage of MPE as a tolerance index was significantly increased in acquisition and expression groups in drugs combination methadone1+haloperidol2 than morphine ones. Also, in dependence group, a marked decrease was shown in withdrawal behaviors in the combination therapy groups. Conclusion: Our results showed that probably methadone and haloperidol combination treatment, especially at a ratio of 1 to 2, could reduce tolerance and dependence more than single drug treatment in animal groups.