The prefrontal cortex is involved in the regulation and control of substance addiction-related cognitive, behavioral, and emotional changes. The present study identified prefrontal cortex protein profiles in morphine-addicted rats; these were subsequently compared with normal rats. Results showed 87 protein spots with differentially expressed levels in the morphine addiction group, with the majority located in meta acid zones at pH 4.2–6.8 and having a molecular weight of 30–110 kDa. In addition, 2 protein spots were identified as being associated with neurotoxicity (Snap25 isoform β-Snap25 of synaptosomal-associated protein 25 and β-actin).