Objective Drug withdrawal has been believed to be associated with dysregulation of reward properties, especially the decrease of sensitivity to the drug previously used.The present study is designed to determine whether prior opiates exposure altered the rewarding sensitivity to opiates used afterwards.Methods We recorded the dopamine (DA) neuron firing activity in ventral tegmental area (VTA) using the electrophysiological in vivo, tested the level of DA metabolites in nucleus accumbens (NAc) using HPLC, and observed the behavioral sensitivity to morphine-induced reward with conditioned place preference (CPP) paradigm.Results (1) A significant withdrawal syndrome was observed at 24 h postwithdrawal in chronic morphine-treated rats, which disappeared 7 d later.(2) Electrophysiological recording the firing activity of VTA DA neurons revealed a dramatic change from early to prolonged withdrawal, representing a transition from tolerance to sensitization and then to normal after 45 d of withdrawal.(3) HPLC analyses showed that the contents of DA and its metabolites in NAc decreased for at least 14 d but increased significantly after 30 d postwithdrawal in response to morphine challenge.(4) Measuring the behavioral sensitivity to morphine rewards using conditioned place preference (CPP) paradigm, we found that only 45 d-SW rats displayed significant preference for the morphine-associated environment, and disrupting general dopamine signaling prevented this morphine-induced CPP.Conclusion Changed sensitivity of VTA-NAc dopaminergic signaling is probably the underlying mechanism for the morphine-induced reward behavior after spontaneous withdrawal.