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 NaV1.8-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.