Neuroinflammation After Musculoskeletal Trauma - Missing Link Between Orthopedic Injury and Chronic Pain?

Musculoskeletal injuries, such as fractures and whiplash, affect around 9 million people annually and are a major cause of disability. In many cases, pain persists despite tissue healing, which is not fully explained by traditional models. Increasing evidence suggests that neuroinflammation - the activation of the innate immune system in the peripheral and central nervous systems - may underlie chronic pain. It involves glial cell activation and the release of proinflammatory mediators, leading to central sensitization and maladaptive synaptic plasticity. To evaluate neuroinflammation as a potential “missing link” between orthopedic injury and chronic pain, and to identify therapeutic targets. A search of PubMed, Web of Science and Google Scholar was conducted. Included were randomized controlled trials, systematic review and meta-analyses of ankle sprain treatment and rehabilitation strategies. Neuroinflammation contributes to the transition from acute to chronic pain beyond tissue healing. Glial activation and mediators, such as TNF-α and IL-1β, drive central sensitization, while caspase cascades (caspase-1, -3, -6) regulate AMPA and NMDA receptor trafficking in the spinal cord, maintaining hypersensitivity. Clinical findings, including MRI studies of whiplash patients, demonstrate nerve root inflammation associated with hyperalgesia. Emerging therapies, such as transcutaneous vagus nerve stimulation (tVNS) and exosome-based approaches, show promise in modulating these processes. Neuroinflammation links musculoskeletal injury to persistent pain by combining immune activation and neural changes that sustain central sensitization. Understanding these mechanisms may help identify patients at risk and guide the development of treatments targeting neuroinflammation to prevent chronic pain.