Virtual screening of GPR37L1 small-molecule modulator for neuropathic pain

Accumulating evidence indicates that glial cells play a critical role in the initiation, maintenance, and resolution of neuropathic pain. However, there is lack of glia-specific molecular targets for pain management. We recently identified the G protein-coupled receptor GPR37-like 1 (GPR37L1) as a glia-selective receptor expressed in astrocytes and satellite glial cells (SGCs), and GPR37L1 protects against the development of neuropathic pain, highlighting it as a promising target for neuroglial modulation. Building on our discovery that the proresolving lipid mediator Maresin1 acts as an endogenous ligand for GPR37L1, this study aimed to identify small-molecule GPR37L1 agonists with improved synthetic accessibility and analgesic duration. Using virtual screening combined with molecular dynamics simulations, we identified compound P06 as a top candidate with the highest predicted binding affinity. In vitro, P06 induced a dose-dependent potassium influx in cells expressing GPR37L1. The analgesic efficacy of P06 was evaluated in mouse models of neuropathic pain after chemotherapy-induced peripheral neuropathy and spared nerve injury (SNI). A single intrathecal injection of P06 produced robust and long-lasting inhibition of chemotherapy-induced mechanical allodynia for more than 24 hours. This effect was completely abolished in Gpr37l1 knockout mice, confirming a receptor-dependent mechanism. P06 also alleviated SNI-induced mechanical/cold allodynia and mitigated nerve injury-induced reactive gliosis in SGCs of dorsal root ganglia. Mechanistically, P06 directly acted on human and mouse SGCs to enhance potassium levels and suppress paclitaxel-induced Interleukin-1β release. Together, these findings establish GPR37L1 as a glia-specific therapeutic target and demonstrate that small-molecule activation of GPR37L1 provides effective relief from neuropathic pain.