FM‐dye inhibition of Piezo2 relieves mechanically evoked pain in mouse models of acute inflammatory and osteoarthritic knee pain

Background and Purpose Musculoskeletal pain is a significant burden with limited pain relief options. The mechanically activated ion channel Piezo2 plays a role in mechanical sensitization; however, there has been little progress in examining therapeutics that target Piezo2. The goal of this study was to assess the effectiveness of FM‐dye in reducing acute inflammatory and osteoarthritic (OA) knee pain in mice through Piezo2. Experimental Approach Wild‐type or nociceptor‐specific Piezo2 conditional knockout (Piezo2cko) mice were used. The complete Freund's adjuvant (CFA) model of acute inflammatory knee pain, the partial medial meniscectomy (PMX) OA model, and ageing‐associated OA mouse models were used. Pain‐related behaviours (knee hyperalgesia, weight bearing asymmetry) were established prior to intra‐articular injection of FM‐dye (5 nmol in 2.5 μl) or vehicle. In vivo calcium imaging of the L4 dorsal root ganglion (DRG) was performed using Na V 1.8‐GCaMP6 mice in the CFA model. Key Results In the CFA model, female and male mice intra‐articularly injected with FM1‐43 exhibited reduced knee hyperalgesia 90 min post‐injection. In vivo calcium imaging of the DRG demonstrated a reduction in nociceptor responses to mechanical force applied to the knee of CFA mice following FM‐dye. Following PMX, intra‐articular injection of FM1‐43 reduced knee hyperalgesia in wild‐type mice but not in Piezo2cko mice; weight bearing asymmetry was also reduced. In mice with age‐associated OA, intra‐articular injection of FM‐dyes reduced knee hyperalgesia. Conclusion and Implications Inhibiting Piezo2 pharmacologically reduced pain‐related behaviours in mouse models of inflammatory and OA knee pain, providing evidence of the therapeutic potential of targeting Piezo2.