Single-Nuclei RNA Sequencing Identifies Type C Low-Threshold Mechanoreceptors as Key Players in Paclitaxel-Induced Peripheral Neuropathy

Neuropathic pain triggered by chemotherapy poses a significant clinical challenge. Investigating cell type-specific alterations through single-cell transcriptome analysis holds promise in understanding symptom development and pathogenesis. In this study, we performed single nuclei RNA (snRNA) sequencing of dorsal root ganglions (DRG) to explore the molecular mechanism underlying paclitaxel-induced neuropathic pain. Mouse exposed to repeated paclitaxel doses developed persistent pain hypersensitivity lasting at least 21 days. The snRNA sequencing unveiled seven major cell types within DRGs, with neurons further subdivided into 12 distinct subclusters using known markers. Notably, type C low-threshold mechanoreceptors (C_LTMR) exhibited the most pronounced transcriptomic changes post-paclitaxel administration. Differential gene expression and Gene Ontology (GO) analysis highlighted suppressed potassium-related currents, microtubule transport, and mitochondrial functions in C_LTMR following paclitaxel treatment. Meanwhile, Gene Set Enrichment Analysis (GSEA) suggested increased Interleukin 17 production in C_LTMR after paclitaxel exposure. Pseudo-time analysis uncovered nine distinct states (state 1 to 9) of C_LTMR. State 1 exhibits higher prevalence in paclitaxel-treated mice and altered neurotransmission properties, likely contributing to paclitaxel-induced pain hypersensitivity. This comprehensive exploration sheds light on the molecular mechanisms driving paclitaxel-induced neuropathic pain, offering potential avenues for therapeutic intervention.