Abstract: Objective: To investigate the effect of Peroxisome proliferator-activated receptor γ(PPARγ) agonist Pioglitazone on pain behavior and mitochondrial oxidative stress of spinal dorsal horn microglia in rats with neuropathic pain. Methods: Forty SD male rats were divided into four groups according to random number table method: sham operation(sham) + solvent dimethyl sulfoxide group(DMSO, S + D group), sham + Pioglitazone group(S+P group), sciatic nerve ligation(CCI)+solvent DMSO group(I+D group) and CCI+Pioglitazone group(I+P group). The neuropathic pain model was established by CCI surgery, and corresponding drugs were injected intrathecally on the 7th to 14th day after CCI. The paw withdrawal mechanical threshold(PWMT) and paw withdrawal thermal latency(PWTL) of rats in each group were measured before operation(T₀) and on the 3rd(T₁),7th(T₂) and 14th(T₃) day after operation. The spinal cord and lumbar enlargement specimens of rats were taken on the 14th day after operation. The activation of microglia was observed by immunofluorescence technique. The mitochondrial damage of microglia was observed by transmission electron microscopy. The expression of NRF1,a key regulatory factor of mitochondrial biogenesis, was determined by western blotting. Mitochondrial DNA(mtDNA) content was detected by reverse transcription-quantitative polymerase chain reaction(RT-qPCR). The levels of reactive oxygen species(ROS) were detected by oxide anion probe. The activity of superoxide dismutase(SOD) and the level of malondialdehyde(MDA) in each group were detected. The expression of inflammatory factors IL-1β, IL-6 and TNF-α was detected by enzyme-linked immunosorbent assay(ELISA). Results: Compared with the I+D group, PWMT and PWTL in the I+P group were significantly increased at T₂-T₃ after administration(P<0.05), and the activation of spinal dorsal cornea microglia was decreased(P<0.05). Transmission electron microscopy showed that mitochondrial structure was improved, and the contents of ROS and MDA were decreased(P<0.05). SOD activity was increased(P<0.05), mitochondrial NRF1 and mtDNA expression was increased(P<0.05), and inflammatory factors IL-1β, IL-6 and TNF-α expression levels were decreased(all P<0.05). Conclusion: Intrathecal injection of Pioglitazone can alleviate neuropathic pain in rats, and its mechanism may be related to the inhibition of abnormal activation of microglia, protection of mitochondrial function of microglia, reduction of oxidative stress and thus reducing inflammation.