Morphine tolerance involes numerous and complex mechanisms.The heterodimerization of mu and delta opioid receptors put forward recently is one of the important mechanisms which could cause the development of opiate tolerance.When transported to the membrance of neural cells,delta opioid receptors(DOR) can combine with mu opioid receptors(MOR) to form MOR-DOR heterodimers,leading to the formation of new signaling pathway.This novel mechanism can clarify the critical role of DOR in the development of morphine tolerance.In this review,we analyze the regulation of DOR on MOR function during morphine tolerance in light of the recent findings with the regulation of DOR trafficking and the new complex :MOR-DOR heterodimer.