Transient Receptor Potential Melastatin 3 ion channel expressed in sensory neurons mediates osteoarthritis pain in mice

Objective: Osteoarthritis (OA) is a degenerative joint disease characterized by chronic pain.We investigated whether the ion channel transient receptor potential melastatin 3 (TRPM3), expressed in sensory neurons, mediates OA pain. J o u r n a l P r e -p r o o fDesign: We used genetically modified mice, pharmacological tools, and behavioural assessments to evaluate the role of TRPM3 in OA pain induced by monosodium iodoacetate (MIA) or partial medial meniscectomy (PMM).Global Trpm3 knockout (Trpm3 -/-) and conditional deletion in sensory neurons (Advillin-Cre/Trpm3 fl/fl ) were compared with control mice.Selective TRPM3 antagonists (ononetin and isosakuranetin) were tested for their ability to reverse established pain.Histological analyses were performed to assess cartilage damage.Results: Global deletion of Trpm3 prevented the development of pain behaviours in both MIA (mean difference [MD] = -7.8,95% CI: -13.6 to -2.1) and PMM (MD = -13.6,95% CI: -22.3 to -4.9) models without inhibiting structural cartilage damage.Sensory neuron-specific Trpm3 deletion replicated this effect in PMM mice (MD = -9.0,95% CI: -15.0 to -3.1), demonstrating a neuronal contribution.Furthermore, pharmacological inhibition of TRPM3 with ononetin (MIA: MD = -2.8,95% CI: -4.4 to -1.4; PMM: MD = -1.5, 95% CI: -2.2 to -0.7) or isosakuranetin (MIA: MD = -3.0,95% CI: -4.4 to -1.6; PMM: MD = -1.5, 95% CI: -2.2 to -0.8) reversed established mechanical hypersensitivity in OA mice.Conclusions: TRPM3 expressed in sensory neurons is a critical mediator of OA pain in mice.Selective TRPM3 antagonism effectively alleviates established pain, supporting this channel as a potential therapeutic target for chronic pain associated with OA.