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Here, we demonstrate the analgesic actions of PDX in a mouse model of tibial fracture\u2013induced postoperative pain (fPOP). Intravenous early- and late-phase treatment of PDX (100 ng\/mouse) effectively alleviated fPOP. Compared with protectin D1 (PD1)\/neuroprotectin D1, DHA, steroids, and meloxicam, PDX provided superior pain relief. While dexamethasone and meloxicam prolonged fPOP, PDX shortened the pain duration. The analgesic effects of PDX were abrogated in\n                    <jats:italic>Gpr37<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice, which displayed deficits in fPOP resolution. PDX was shown to bind GPR37 and induce calcium responses in peritoneal macrophages. LC-MS\/MS\u2013based lipidomic analysis revealed that endogenous PDX levels were approximately 10-fold higher than those of PD1 in muscle at the fracture site. PDX promoted macrophage polarization via GPR37-dependent phagocytosis and efferocytosis through calcium signaling in vitro, and it further enhanced macrophage viability and efferocytosis in vivo via GPR37. Finally, PDX rapidly modulated nociceptor neuron responses by suppressing C-fiber\u2013induced muscle reflex in vivo and calcium responses in DRG neurons ex vivo and by reducing TRPA1\/TRPV1-induced acute pain and neurogenic inflammation in vivo. Our findings highlight multiple benefits of PDX to manage postoperative pain and promote perioperative recovery.\n                  <\/jats:p>","DOI":"10.1172\/jci190754","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:00:54Z","timestamp":1768503654000},"source":"Crossref","is-referenced-by-count":7,"title":["Protectin DX resolves fracture-induced postoperative pain in mice via neuronal signaling and GPR37-activated macrophage efferocytosis"],"prefix":"10.1172","volume":"136","author":[{"given":"Yize","family":"Li","sequence":"first","affiliation":[{"name":"Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9092-0075","authenticated-orcid":true,"given":"Sangsu","family":"Bang","sequence":"additional","affiliation":[{"name":"Center for Translational Pain Medicine, 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