{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T14:08:48Z","timestamp":1793110128041,"version":"4.5.0"},"reference-count":44,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T00:00:00Z","timestamp":1700524800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Resolvin D2 (RvD2), an endogenous lipid mediator derived from docosahexaenoic acid, has been demonstrated to have analgesic effects. However, little is known about the mechanism underlying RvD2 in pain relief. Herein, we demonstrate that RvD2 targeted the P2X3 receptor as an analgesic. The electrophysiological activity of P2X3 receptors was suppressed by RvD2 in rat dorsal root ganglia (DRG) neurons. RvD2 pre\u2010application dose\u2010dependently decreased \u03b1,\u03b2\u2010methylene\u2010ATP (\u03b1,\u03b2\u2010meATP)\u2010induced inward currents. RvD2 remarkably decreased the maximum response to \u03b1,\u03b2\u2010meATP, without influencing the affinity of P2X3 receptors. RvD2 also voltage\u2010independently suppressed ATP currents. An antagonist of the G protein receptor 18 (GPR18), O\u20101918, prevented the RvD2\u2010induced suppression of ATP currents. Additionally, intracellular dialysis of the G\u03b1<jats:sub>i\/o<\/jats:sub>\u2010protein antagonist pertussis toxin (PTX), the PKA antagonist H89, or the cAMP analog 8\u2010Br\u2010cAMP also blocked the RvD2\u2010induced suppression. Furthermore, \u03b1,\u03b2\u2010meATP\u2010triggered depolarization of membrane potential along with the action potential bursts in DRG neurons were inhibited by RvD2. Lastly, RvD2 attenuated spontaneous nociceptive behaviors as well as mechanical allodynia produced by \u03b1,\u03b2\u2010meATP in rats via the activation of the peripheral GPR18. These findings indicated that RvD2 inhibited P2X3 receptors in rat primary sensory neurons through GPR18, PTX\u2010sensitive G\u03b1<jats:sub>i\/o<\/jats:sub>\u2010proteins, and intracellular cAMP\/PKA signaling, revealing a novel mechanism that underlies its analgesic effects by targeting P2X3 receptors.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16009-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.16009","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T18:38:24Z","timestamp":1700678304000},"page":"3715-3726","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Lipid mediator resolvin <scp>D2<\/scp> inhibits 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