Neuroprotectin D1 and GPR37 protect against chemotherapy-induced peripheral neuropathy and the transition from acute to chronic pain.

Chemotherapy-induced peripheral neuropathy (CIPN) significantly impacts patient's quality of life and complicates cancer treatment. Neuroprotectin D1 (NPD1)/protectin D1 (PD1), derived from docosahexaenoic acid (DHA), exhibits analgesic actions in animal models of inflammatory pain and neuropathic pain. GPR37, a receptor for NPD1/PD1, is known to regulate macrophage phagocytosis and inflammatory cytokine expression, but its role in primary sensory neurons and CIPN remains poorly understood. We found Gpr37 mRNA expression in both neurons and macrophages in mouse dorsal root ganglia (DRG), furthermore, GPR37 is downregulated by the chemotherapy agent paclitaxel. Gpr37 mRNA was notably high in neonatal mouse DRG neurons. In contrast, Gpr37l1 is primarily expressed by satellite glial cells in DRG. Chemotherapy-induced neuropathic pain symptom (mechanical allodynia) resolved within seven weeks in wild-type mice, but it persisted in Gpr37 knockout mice, highlighting GPR37's role in acute-to-chronic pain transition. Consistently, intra-DRG knockdown of Gpr37 in naive animals was sufficient to induce mechanical allodynia. In primary DRG cultures, NPD1 facilitated neurite outgrowth of sensory neurons in the presence of paclitaxel, in a GPR37-dependent manner. NPD1 treatment also mitigated mechanical allodynia and prevented the loss of intraepidermal nerve fibers in hind paw skins in wild-type mice undergoing chemotherapy, but these protective effects are absent in Gpr37 knockout mice. Finally, spatial transcriptomics analysis revealed macrophage and neuronal expression of GPR37 in human DRG. Our findings indicate that GPR37 deficiency drives pain chronicity in CIPN. This study also underscores the potential of NPD1 in safeguarding against sensory neuron degeneration and neuropathic pain in CIPN through GPR37.