Although there are clear interactions between circadian rhythms and drug addiction, mechanisms for such interactions remain unknown. Studies have shown that the circadian clock gene Period in Drosophila melanogaster could influence behavioral responses to cocaine, and the mouse homologues, mPer1 and mPer2, modulate cocaine sensitization and reward. In the present study, we applied DNAzyme targeting mPer1 to interfere the expression of mPer1 in CNS in mice, and studied its effects on morphine-induced reward and its molecular mechanism. The results demonstrated that the DNAzyme could attenuate the expression of mPer1 in CNS in mice and downregulate the increased extracellular signal-regulated kinase (ERK) activity induced by morphine in whole brain and the nucleus accumbens, the key region of drug addiction. Mice treated with morphine and injected intracerebroventricularly with DNAzyme did not show preference to the morphine-trained side. These results indicate that drug dependence seems to be influenced at least partially by mPer1 and its mechanism may involve the ERK signal pathway.