C-LTMRs Regulate Thermosensation and Gate the Transition from Acute to Chronic Pain

Abstract

C-low threshold mechanoreceptors (C-LTMRs) are traditionally associated with affective touch, yet emerging evidence suggests broader roles in sensory processing and pain modulation. We developed an intersectional genetic approach to selectively ablate C-LTMRs in adult mice by combining Nav1.8IRES-FLPo and THCreER drivers with a conditional DTR reporter. This approach yields robust, tissue-specific deletion of C-LTMRs without off-target effects in non-sensory tissues. C-LTMR-ablated mice exhibit altered thermotaxis behavior, including a sharpened and spatially restricted preference for warmth, while maintaining largely intact responses to touch. Remarkably, following surgical or chemotherapeutic injury, these mice display persistent mechanical and cold hypersensitivity, implicating C-LTMRs in the resolution of pain. Transcriptomic profiling of dorsal root ganglia (DRG) and dorsal horn of the spinal cord (DHSC) revealed widespread transcriptional dysregulation in pathways related to extracellular matrix remodeling, vascular function and gliogenesis in naive mice. In C-LTMR-ablated mice, paclitaxel failed to induce pro-recovery transcriptional programs and instead promoted persistent neuroinflammatory signatures. These findings establish C-LTMRs as key modulators of pain recovery, acting through tissue-specific transcriptional programs that suppress inflammation and support sensory homeostasis.