The cation channel Trpa1 and chemokine Cxcl1 mediate axonal degeneration in spared nerve injury-induced neuropathic pain.

Demyelination of peripheral nerve injury is a vital cause of neuropathic pain. Schwann cells play an important role in supporting and maintaining the removal and regeneration of myelin debris from neuronal axons in the peripheral nervous system. Creating a good immune microenvironment would promote the Schwann cells to repair the injured nerve and reverse the allodynia of neuropathic pain. Trpa1, a transient receptor potential ion channel, and Cxcl1, a chemokine, play crucial roles in allodynia in pain pathophysiology. However, their interaction in neuropathic pain remains unclear. This study aimed to elucidate the role of Trpa1 in neuropathic pain and its interaction with Cxcl1. Using a spared nerve injury model in mice, mechanical allodynia was observed alongside increased Trpa1 expression in injured nerves. Treatment with a Trpa1 inhibitor alleviated allodynia, suggesting Trpa1 is involved in neuropathic pain. Transcriptome sequencing revealed immune pathway enrichment post-Trpa1 inhibition. Cxcl1 recruited Cxcr2-positive macrophages to injured sites, whereas Trpa1 inhibition reduced Cxcl1 expression and Cxcr2 recruitment in Schwann cells and in neurons. In addition, Mag (myelin-associated glycoprotein), crucial for axonal stability, was downregulated in the spared nerve injury model but increased post-Trpa1 blockade, indicating Trpa1 plays an important role in the Cxcl1-mediated immune cascade in axonal degeneration. In summary, neuronal and dedifferentiated Schwann cell Trpa1 regulates Cxcl1 synthesis, recruiting macrophages to nerve injury sites and mediating neuropathic pain. Collectively, our findings suggest that Trpa1 activation weakens axonal resistance to degeneration by inhibiting Mag. This study highlights the multifaceted involvement of Trpa1 in neuropathic pain, suggesting a potential therapeutic target for neuropathic pain management.