Recent studies suggest that neuromodulation regulates inflammation and neuroinflammation through neuro-immune interactions and highlight possible involvement of specialized proresolving mediators (SPMs, Tao et al., 2020). Auricular electrostimulation has been used to treat headaches. Resolvin D2 (RvD2) is a SPM derived from DHA and exhibits potent analgesic actions in different pain models. RvD2 was shown to reduce pain and inflammation via GPR18. In the present study, we investigated the role of RvD2-GPR18 axis in mediating the protective effect of auricular electrostimulation on lipopolysaccharide (LPS)-induced inflammation, hyperalgesia, and cognitive dysfunction in CD1 mice. It was observed that the rectal temperature decreased at two hours after intraperitoneal (i.p.) injection of LPS (1 mg/kg, 10 mg/kg, respectively), and this hypothermia was prevented by auricular electrostimulation. Auricular electrostimulation also prevented LPS-induced increases in serum levels of IL-1β and IL-6. Interestingly, auricular electrostimulation increased RvD2 level in the CSF of LPS-treated mice. LPS treatment (10 mg/kg) also resulted in mechanical hypersensitivity and cognition index decrease, and both can be reversed by auricular electrostimulation and intrathecal injection of RvD2 (100 ng/mice). Intrathecal injection of O-1918, an antagonist of GPR18, blocked the protective effect of RvD2 in LPS-induced hypothermia. Our results showed that auricular electrostimulation might protect against LPS-induced inflammation, hyperalgesia, and cognitive dysfunction via RvD2-GPR18 axis. Duke University Anesthesiology research fund.