Protectin DX resolves fracture-induced postoperative pain in mice via neuronal signaling and GPR37-activated macrophage efferocytosis

Protectin DX (PDX) is a member of the superfamily of specialized pro-resolving mediators (SPMs) and exerts anti-inflammatory actions in animal models; but the specific signaling pathways involved in its actions have not been fully elucidated. Here we demonstrate the analgesic actions of PDX in a mouse model of tibial fracture-induced postoperative pain (fPOP) via activation of GPR37. Intravenous early-phase and late-phase treatment of PDX (100 ng/mouse) effectively alleviated fPOP. Compared to protectin D1/neuroprotectin D1, DHA, steroid, and meloxicam, PDX produced superior pain relief. While dexamethasone and meloxicam prolonged fPOP, PDX shortened the pain duration. The analgesic effects of PDX were abrogated in Gpr37 ^−/− mice, which displayed deficits in fPOP resolution. PDX binds GPR37 and induces calcium responses in peritoneal macrophages. LC-MS-MS-based lipidomic analysis revealed that endogenous PDX levels were ∼10-fold higher than PD1 in muscle at the fracture site. PDX promotes macrophage polarization via GPR37-dependent phagocytosis and efferocytosis through calcium signaling in vitro , and it further enhances macrophage viability and efferocytosis in vivo via GPR37. Finally, PDX rapidly modulates nociceptor neuron responses by suppressing C-fiber-induced muscle reflex in vivo and calcium responses in DRG neurons ex vivo and 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.