BACKGROUND The aim of this study was to detect differentially expressed proteins in the nucleus accumbens between the states of extinction and reinstatement ofmorphine addiction. Numerous studies on the neurobiological mechanisms concerning drug craving and relapse have been reported to date, but data on their relationship with the underlying key molecular mechanisms involved remain limited. METHODS In this study, 40 male Sprague-Dawley rats were equally randomized into a saline group and a morphine group. Both groups received drug self-administration training, after which extinction models were established naturally. The groups were further divided into two subgroups for extinction and reinstatement tests. Cerebral nucleus accumbens masses were measured for total protein extraction. Two-dimensional electrophoresis was performed to determine differential protein spots. These differential proteins were then enzymolysed and identified using mass spectrography. RESULTS The proteins were classified as fatty acid-binding protein, serine/threonine protein phosphatase 2A catalytic subunit beta isoform, serine/threonine protein phosphatase 2A catalytic subunit alpha isoform, serine/threonine protein phosphatase 2A regulatory subunit B2 subunit gamma or heat shock protein 90 co-chaperone CDC37. CONCLUSION Significant changes in five proteins were detected between extinction and reinstatement. These proteins are correlated with phosphorylation and the tricarboxylic acid cycle.