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• K ATP channel opening could relief chronic pain. • K ATP channel opening activates the Gas6/Axl/SOCS3 axis to induce inflammatory tolerance. • K ATP channels could be a target for attenuating chronic pain. Current treatments for chronic pain are unsatisfactory, therefore, new therapeutics are urgently needed. Our previous study indicated that K ATP channel openers have analgesic effects, but the underlying mechanism has not been elucidated. We speculated that K ATP channel openers might increase suppressor of cytokine signaling (SOCS)-3 expression to induce inflammatory tolerance and attenuate chronic pain. Postoperative pain was induced by plantar incision to establish a chronic pain model. Growth arrest–specific 6 (Gas6)−/− and Axl−/− mice were used for signaling studies. The microglia cell line BV-2 was cultured for the in vitro experiments. The K ATP channel opener significantly attenuated incision-induced mechanical allodynia in mice associated with the upregulated expression of SOCS3. Opening K ATP channels induced the expression of SOCS3 in the Gas6/Axl signaling pathway in microglia, inhibited incision-induced mechanical allodynia by activating the Gas6/Axl-SOCS3 signaling pathway, and induced inflammatory tolerance to relieve neuroinflammation and postoperative pain. We demonstrated that opening of the K ATP channel opening activated Gas6/Axl/SOCS3 signaling to induce inflammatory tolerance and relieve chronic pain. We explored a new target for anti-inflammatory and analgesic effects by regulating the innate immune system and provided a theoretical basis for clinical preemptive analgesia. [ABSTRACT FROM AUTHOR]