EXPRESS: Evodiamine attenuates chemotherapy-induced peripheral neuropathy by mediating macrophage M2 polarization and inhibiting the upregulation of the p38 MAPK-TRPV1 axis in rat dorsal root ganglia

Purpose: To investigate evodiamine's analgesic effects and molecular mechanisms on chemotherapy-induced peripheral neuropathy (CIPN), focusing on the p38/MAPK-TRPV1 signaling axis and macrophage polarization in dorsal root ganglia (DRG). Methods: A paclitaxel-induced CIPN rat model was established with behavioral assessments via von Frey and thermal hyperalgesia tests. TRPV1, TRPV4, and inflammatory cytokine expression were analyzed using qRT-PCR, ELISA, and Western blot. Macrophage infiltration and polarization were evaluated by flow cytometry and immunofluorescence. Mechanistic studies utilized macrophage-conditioned media from RAW264.7 cells and clodronate liposome-mediated macrophage depletion to establish causal relationships between macrophage polarization and nociceptive behavior. Results: Evodiamine dose-dependently alleviated paclitaxel-induced mechanical and thermal allodynia both acutely and preventively. It selectively inhibited upregulation of TRPV1 without affecting TRPV4 and reduced pro-inflammatory cytokine levels (TNF-α, IL-1β, IL-6, MCP-1) in the DRG. Evodiamine significantly reduced F4/80+ macrophage infiltration and shifted macrophage polarization from a pro-inflammatory M1 phenotype (decreased MCP1, CD86) to an anti-inflammatory M2 phenotype (increased CD163, CD206). Notably, macrophage-conditioned medium experiments revealed that evodiamine indirectly modulates neuronal TRPV1 expression through macrophage-derived factors. Furthermore, evodiamine attenuated paclitaxel-induced p38 MAPK phosphorylation in DRG neurons, with selective p38 MAPK inhibition by SB203580 confirming this pathway's critical involvement in TRPV1 regulation and pain modulation. Conclusion: Evodiamine alleviates CIPN through a novel neuroimmune mechanism involving M2 macrophage polarization and inhibition of the p38/MAPK-TRPV1 axis in DRG neurons. These findings establish macrophage polarization as a key therapeutic target and highlight evodiamine's potential as a natural therapeutic agent for CIPN management.