Wnt5a in keratinocytes contributes to complex regional pain syndrome through the activation of NR2B and MMP9 in rats

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BACKGROUND: Complex regional pain syndrome (CRPS) is a chronic pain condition characterized by inflammatory features, though the underlying mechanisms remain partly understood. Our study examined whether Wnt5a in skin keratinocytes contributes to CRPS-related pain hypersensitivity by activating downstream N-methyl-D-aspartate receptor subunit 2B (NR2B) and matrix metalloproteinase-9 (MMP9) signaling in rats. METHODS: We developed a cell-culture model to mimic the local inflammation of CRPS and a rat model to mimic the chronic post-ischemia pain experienced by CRPS patients. Mechanical and heat pain thresholds in the hind paw were measured using an electronic von Frey apparatus and a radiant heat device. Western blotting and immunofluorescence were used to examine the expressions of NR2B and MMP9 in the skin and dorsal root ganglion (DRG), and immunofluorescence staining of connexin 43 (Cx43) and protein gene product 9.5 (PGP9.5) were conducted to explore the interaction between keratinocytes and nerve fibers in the skin. RESULTS: In cell culture, Wnt5a was expressed in keratinocytes and contributed to cellular injury by increasing the levels of NR2B and MMP9. The mechanical and heat pain thresholds measured in the hind paw were decreased in CRPS rats, indicating increased pain sensitivity. The inhibition of Wnt5a alleviated these CRPS-related pain hypersensitivities. High levels of Cx43 and PGP9.5 staining were observed in the epidermis of CRPS rats, suggesting an interaction between keratinocytes and nerve fibers that may contribute to CRPS. Additionally, upregulations of NR2B and MMP9 in the DRG may further exacerbate pain. CONCLUSIONS: Skin keratinocytes may play an essential role in the pathophysiology of CRPS. Wnt5a signaling may increase pain sensitivity by upregulating downstream NR2B and MMP9, thereby contributing to CRPS.

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