Tissue Accumulation of Neutrophil Extracellular Traps Mediates Muscle Hyperalgesia in a Mouse Model

Accumulation of uric acid (UA) during muscular trauma is a causative factor involved in the development of muscle hyperalgesia. Neutrophil extracellular traps (NETs), DNA-based reticular structures to capture UA, play a central role in the pain onset of gout attacks; however, the involvement of NETs via the elevation of local UA level in muscle hyperalgesia due to overuse injuries remains unknown. The triceps surae muscles (TSMs) in the unilateral hindlimb of mice were electrically stimulated to induce excessive muscle contraction. Mechanical withdrawal thresholds, tissue UA levels, neutrophil recruitment, protein amount of citrullinated histone 3 (citH3), a major marker of NETs, were investigated. Furthermore, whether neutrophil depletion, extracellular DNA cleavage, and administration of the urate-lowering agent febuxostat could improve muscle hyperalgesia due to NET formation was examined. CitH3 expression upon neutrophil recruitment significantly increased in the stimulated TSMs with an increase in tissue UA levels, whereas febuxostat administration improved muscle hyperalgesia with decreases in citH3 and tissue UA levels, as observed in neutrophil depletion and extracellular DNA digestion. The underlying mechanism of muscle hyperalgesia associated with locally recruited neutrophils forming NETs due to the increased tissue UA levels potentially plays a significant role in creating a vicious circle of muscle pain.