Blockade of morphine‐induced behavioral sensitization by a combination of amisulpride and RB101, comparison with classical opioid maintenance treatments

Background and purpose: Maintenance treatments with methadone or buprenorphine are more or less efficient procedures for helping heroin addicts to stop or reduce drug abuse. Another approach to treat opiate dependence could be to target the endogenous opioid system by enhancing the effects of enkephalins by protecting them from enzymic degradation by the dual peptidase inhibitor RB101. Experimental approach: As chronic treatment with the dopamine D2 antagonist amisulpride facilitates RB101‐induced behavioral effects, we chose in this study to treat mice previously sensitized to the hyperlocomotor effects induced by morphine with a combination of amisulpride and RB101. Key results: Expression of morphine‐induced locomotor sensitization was abolished after combined treatment with amisulpride (20 mg.kg −1 , i.p.) and RB101 (80 mg.kg −1 , i.p.), whereas these drugs were not effective when used alone. We then compared these results with the effects of amisulpride combined with buprenorphine (0.1 mg.kg −1 , i.p.) or methadone (2.5 mg.kg −1 , i.p.) upon morphine‐induced behavioral sensitization. Whereas the combination of amisulpride and buprenorphine partially blocked the expression of morphine sensitization, amisulpride+methadone was not effective in this paradigm. Conclusions and implications: The combination of amisulpride+RB101 appears to be very efficient in blocking the expression of morphine‐induced behavioral sensitization. This could reflect a reinstatement of a balance between the function of the dopamine and opioid systems and could represent a new approach in maintenance treatments for opiate addiction. British Journal of Pharmacology (2007) 151 , 75–83. doi: 10.1038/sj.bjp.0707195