{"paper_id":"4d0af56b-2ffc-4bd8-aae8-d3b4256d1de7","body_text":"Abstract\nChronic pain arises when dorsal root ganglion (DRG) neurons become sensitised to noxious inputs, a process driven by inflammatory mediators such as prostaglandin E2 (PGE2). Local translation of axonal mRNAs is a key regulator of nociceptor plasticity, yet how axonal transcriptome dynamics contribute to inflammatory sensitisation remains unclear. Using compartmentalised culture systems and RNA-sequencing, we defined axonal and somatic transcriptomes in embryonic (E16.5) and adult (W8) DRG neurons and assessed their remodelling after PGE2 exposure. We identify a conserved core axonal transcriptome spanning embryonic to adult stages, prominently enriched for ribosomal and mitochondrial functions, consistent with sustained translational and metabolic demands. PGE2 elicited compartment-specific reprogramming: pathways related to sensory processing and pain were upregulated in axons but downregulated in somata. Functionally, prolonged axonal PGE2 exposure enhanced capsaicin-evoked Ca²⁺ responses and drove retrograde sensitisation of neuronal somata. Integrating transcriptomics with functional assays, we pinpointed Tnfrsf12a (Fn14), a cytokine receptor linked to regeneration and neuropathic pain, as a PGE2-induced axonal mRNA. Crucially, local axonal knockdown of Tnfrsf12a significantly reduced neuronal excitability, providing proof-of-concept that axonally enriched transcripts can be targeted to modulate sensitisation. These findings position conserved axonal transcriptome programmes as drivers of peripheral sensitisation and establish Tnfrsf12a as a therapeutic candidate for inflammatory pain.\nCompeting Interest Statement\nThe authors have declared no competing interest.\nFootnotes\nBio Project ID for SRA repository now provided, plus update on description of Methods.","source_license":"CC-BY-4.0","license_restricted":false}