Inflammatory Mechanisms in Chronic Musculoskeletal Pain

Chronic musculoskeletal pain arises from a complex interplay of peripheral and central inflammatory processes. Tissue injury or repetitive strain triggers infiltration of innate immune cells, notably macrophages, that release pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). These mediators sensitize peripheral nociceptors and promote local fibrosis in muscles, tendons and fascia. Sustained peripheral input drives central sensitisation in the spinal cord and brain, leading to persistent pain amplification and altered neuroimmune communication. A relative deficit in anti-inflammatory signals, including interleukin-10 (IL-10), further skews the balance towards chronic inflammation. Animal models of repetitive overuse illustrate force- and repetition-dependent changes in cytokine expression, connective-tissue remodelling and declines in grip strength, while human studies reveal that systemic markers of low-grade inflammation correlate with pain severity and functional impairment. Advances in biomarker discovery and imaging are beginning to identify patient subgroups who may benefit from targeted anti-inflammatory, rehabilitative or lifestyle interventions, underscoring the global importance of deciphering these mechanisms for improved clinical outcomes.

Research from Nature Portfolio

Recent studies have explored the immediate neuroimmune effects of manual therapies in non-specific neck pain. One randomised placebo-controlled trial assessed whole-blood concentrations of IL-1β and TNF-α at 10 minutes and two hours after spinal mobilisation or a sham procedure. Although manual mobilisation produced substantial short-term pain relief, no systemic changes in primary cytokines were detected. These findings suggest that pain reduction arises from local or central neuroimmune interactions rather than measurable shifts in circulating inflammatory mediators, and highlight the need for future research to focus on tissue-specific and time-dependent inflammatory responses.

Inflammatory Mechanisms in Chronic Musculoskeletal Pain publication trend

The graph below shows the total number of articles in inflammatory mechanisms in chronic musculoskeletal pain across all publications each year (not limited to Nature Index journals).

Technical terms

Cytokine: Small protein released by immune cells that modulates inflammation and pain signalling.

Pro-inflammatory cytokine: Mediator (e.g., IL-6, TNF-α) that promotes leukocyte recruitment and pain sensitisation.

Anti-inflammatory cytokine: Mediator (e.g., IL-10) that limits excessive immune activation and supports tissue repair.

Peripheral sensitisation: Increased responsiveness of nociceptors at the site of tissue injury or inflammation.

Central sensitisation: Amplification of pain signals in the spinal cord and brain leading to heightened pain perception.

Fibrosis: Excessive deposition of collagen and matrix proteins in tissues, contributing to stiffness and pain.

References

1. Immediate systemic neuroimmune responses following spinal mobilisation and manipulation in people with non-specific neck pain: a randomised placebo-controlled trial. Scientific Reports (2023).
2. Poor sleep versus exercise: A duel to decide whether pain resolves or persists after injury. Brain Behavior & Immunity - Health (2023).
3. A systematic review of the role of inflammatory biomarkers in acute, subacute and chronic non-specific low back pain. BMC Musculoskeletal Disorders (2020).
4. Does Low Grade Systemic Inflammation Have a Role in Chronic Pain?. Frontiers in Molecular Neuroscience (2021).
5. Performance of Repetitive Tasks Induces Decreased Grip Strength and Increased Fibrogenic Proteins in Skeletal Muscle: Role of Force and Inflammation. PLOS ONE (2012).
6. The interaction of force and repetition on musculoskeletal and neural tissue responses and sensorimotor behavior in a rat model of work-related musculoskeletal disorders. BMC Musculoskeletal Disorders (2013).