Loss of Schwann Cell Lrp1 Triggers Trigeminal Neuron Sensitization and Orofacial Pain via Mitochondrial and Ion Channel Dysfunction

Orofacial pain affects 10-15% of adults, yet the contribution of Schwann cells to its pathogenesis is poorly understood. Because LRP1 regulates lipid uptake, nerve homeostasis, and repair, we investigated whether Schwann cell LRP1 is involved in trigeminal sensitization and orofacial pain. We generated Schwann cell-specific Lrp1 knockout mice (scLrp1⁻/⁻) and assessed orofacial sensitivity using mechanical and thermal behavioral assays. Schwann cell-neuron interactions were tested using a combination of RNA-seq, Seahorse metabolic flux, biochemical assays, and calcium imaging. TG RNA-seq revealed widespread dysregulation of mitochondrial and metabolic pathways, ROS signaling, calcium homeostasis, and neurodegeneration-related processes, confirmed by metabolic and biochemical analyses. TRPV1 and TRPA1 channels were markedly upregulated and sensitized in TG neurons. LRP1-deficient Schwann cells showed impaired oxidized low-density lipoprotein (oxLDL) uptake and excessive H₂O₂ release, and their conditioned medium induced TRPV1/TRPA1-dependent orofacial hypersensitivity in vivo and neuronal activation in vitro. Schwann cell LRP1 is essential for maintaining mitochondrial function and neuron-glia metabolic coupling in the trigeminal system. Loss of Schwann cell LRP1 alone drives orofacial pain, identifying Schwann cells as active contributors to chronic pain and LRP1 as a promising therapeutic target. Funding: National Institutes of Health/NIDCR (R01 DE033647) and the Department of Defense (W81XWH22-1-0722).