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<div><p>Oxaliplatin (OXA) as the platinum-based agent induces the cumulative neuropathy including functional impairment and neuropathic pain. OXA treatment triggered oxidative stress and inflammatory reaction in the spinal cord. Puerarin as a natural product has the neuroprotective effect on neuropathic pain. Hence, the roles and mechanisms of Pue on OXA induced neuropathic pain were studied. In this study, OXA-induced neuropathic pain mouse model was constructed by oxaliplatin injection for 5 consecutive days and two cycles. Pue (10 mg/kg) was administered intraperitoneally for seven consecutive days. The changes of behavior, morphology and levels of related proteins were detected. As a result, OXA-induced mice exhibited as the increased pain hypersensitivity, the impaired motor coordination, the activated NLRP3 inflammasome mediated inflammation and the suppressed nuclear factor erythroid 2-related factor 2 (Nrf2) mediated antioxidative reaction in the spinal cord (<i>P</i><0.05 vs Control). After Pue administration, the mechanical pain threshold, thermal pain latency, spontaneous pain number and motor latency were improved (<i>P</i><0.05 vs OXA). In the spinal cord, Pue administration reduced the levels of inflammatory elements, increased the levels of antioxidative elements and decreased the levels of oxidative factors (<i>P</i><0.05 vs OXA). Furthermore, Pue also bind with Nrf2 and increased the association of Nrf2 to glutathione peroxidase 4 (GPX4). In summary, Pue alleviates oxaliplatin induced neuropathic pain by enhancing Nrf2/GPX4-mediated antioxidant response and suppressing inflammatory reaction in the spinal cord.</p></div>