Schwann cell Lrp1 deletion drives trigeminal neuron sensitization and orofacial pain by modulating mitochondrial function and TRPV1/TRPA1 activity

Background: Orofacial pain, affecting 10-15% of adults, is a prevalent form of chronic pain that remains a major clinical challenge. The Schwann cell involvement in this pathophysiology is not fully understood. Low-density lipoprotein receptor-related protein 1 (LRP1) in Schwann cells has an unclear role in orofacial pain mechanisms. Findings: We demonstrate that Schwann cell-specific conditional knockout of Lrp1 (scLrp1-/-) in mice leads to pronounced mechanical and thermal hypersensitivity in the orofacial region. RNA-seq of trigeminal ganglia (TG) from scLrp1-/- mice revealed broad changes in mitochondrial and metabolic pathways, reactive oxygen species (ROS) signaling, calcium homeostasis, and neurodegeneration-related processes. Altered mitochondrial function and ROS production in the TG were further confirmed with Seahorse metabolic flux analysis and biochemical assays. Additionally, mechano- and thermos-sensitive ion channels TRPV1 and TRPA1 are overexpressed and sensitized in the TG isolated from scLrp1-/- mice. Schwann cells isolated from scLrp1-/- mice displayed defective oxLDL uptake and excessive H₂O₂ release. Conditioned medium from LRP1 ablated Schwann cells induced orofacial hypersensitivity in vivo and robustly activated TG neurons in vitro in a TRPV1/TRPA1 dependent manner. Conclusions: Our results demonstrate that Schwann cell LRP1 safeguards mitochondrial function and supports neuron-glia metabolic coupling in the trigeminal system. The finding that LRP1 deficiency in Schwann cells drives orofacial pain in the absence of external insults highlights Schwann cells as active drivers, rather than passive amplifiers of chronic pain and identifies LRP1 as a promising target for orofacial pain management.