Overuse injuries spark lasting pain and mood changes through inflammation, rat study finds

New research uncovers how repetitive strain injuries ignite an inflammatory storm, driving both pain and social withdrawal, offering fresh insight into the biological roots of workplace burnout and recovery.

Study: Overuse injury induces persistent behavioral declines that correlate with higher IL-6 expression in the affected musculoskeletal tissues, circulation, and brain. Image Credit: SoftSheep / Shutterstock

In a recent study published in the journal Frontiers in Physiology, a group of researchers investigated whether repetitive reaching injury in mature female Sprague-Dawley rats couples pain-like and sickness behaviors with interleukin-6 (IL-6)-dominated inflammation in musculoskeletal tissues, the circulation, and the brain.

Background

Work-related musculoskeletal disorders (WMSDs) sideline millions of workers each year and drain billions in productivity losses, but still, it is not fully understood how repeating the same physical tasks leads to fatigue, pain, and social withdrawal. Experimental and clinical evidence shows that inflammatory signaling molecules, especially IL-6, surge after tissue damage, and elevated circulating levels are linked with chronic pain and depression. Animal studies further indicate that proinflammatory cytokines can cross the blood-brain barrier (BBB) and disrupt mood-related neural circuits. Key factors include how age, task intensity, and rest periods interact within this neuroimmune dialogue. Further studies should investigate sex-specific effects, fever responses, and long-term functional outcomes.

About the study

Investigators employed a three-arm, randomized, controlled design using mature female Sprague-Dawley rats (14 months of age at the onset). After food restriction, animals were trained under operant conditioning to reach and pull a lever for 6 weeks until they produced about 55% of their maximum voluntary pulling force (MPF). Randomly selected trained rats then performed a high-repetition low-force (HRLF) task for 6 weeks: 2 hours per day, 3 days per week, with a target of 4 reaches per minute at 15% MPF. The remaining trained rats rested, and age-matched food-restricted rats served as the control group. Blinded observers tracked reflexive grip strength, forepaw mechanical sensitivity, social interaction with a juvenile rat, and observed aggression at baseline, after training, and again at week 6. The final group sizes consisted of 24 control rats, 15 trained and rested rats, and 19 task rats. Behavioral scoring was conducted according to standardized protocols to minimize bias.

After 6 weeks of task exposure or matched rest, animals were euthanized, and serum, flexor digitorum muscles, tendons, bones, median nerves, and selected brain regions were collected. Cytokines including interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), IL-6, IL-10, and tumor necrosis factor alpha (TNF-α) were measured by enzyme-linked immunosorbent assay (ELISA). Brain sections were double-labeled for IL-6 with neuronal nuclei antigen (NeuN), glial fibrillary acidic protein (GFAP), or ionized calcium-binding adapter molecule 1 (Iba-1). Data were analyzed using repeated-measures mixed-effects models and Tukey post hoc tests (α = 0.05); planned samples achieved at least 80% statistical power.

Study results

Training resulted in immediate functional costs, as both experimental groups lost approximately 20% of their baseline grip force and became hypersensitive to forepaw stimulation. By week six, rest partially rescued sensation, yet grip weakness lingered, while task animals deteriorated further. They remained 25% weaker than controls, withdrew their paws to monofilaments one-third the original size, and cut prosocial grooming and sniffing time from 40 to 20 seconds. The incidence of boxing or biting rose from nearly 0% in controls and trained rats (who showed only a single instance of aggression) to 42% in task rats. A slight but statistically significant reduction in body weight was also observed in task rats compared to controls at the end of the study. Force-sensor logs revealed that voluntary pull force averaged 27 centinewtons (cN), close to the 15% MPF target, but unsuccessful attempts doubled to more than 300 per two-hour session, intensifying cumulative load.

Biochemical profiling mirrored behavioral severity. Serum IL-1α climbed twofold, TNF-α threefold, and IL-6 fourfold in task rats, whereas the trained + rest group displayed only modest rises in IL-1α and TNF-α, but, crucially, showed no significant increase in IL-6. With the repetitive reaching task, IL-6 increased by 200 to 500% in flexor muscles, forearm bones, and median nerves, while IL-10 declined in muscles, shifting the local balance toward inflammation. Uninvolved tail tissues showed no change, highlighting regional specificity.

Immunohistology identified approximately six IL-6-positive neurons per square millimeter in the rostral cingulate cortex of task rats versus one in controls, alongside dense labeling of ependymal cells and selective activation of the organum vasculosum of the lamina terminalis (OVLT), with a similar, though not statistically significant, trend observed in the subfornical organ (SFO), gateway regions through which blood-borne cytokines influence the brain. Elevated IL-6 and IL-1α in serum or injured tissues correlated inversely with grip strength and positively with mechanical hypersensitivity, reduced sociability, and aggression. Median nerve IL-6 and TNF-α tracked most strongly with pain metrics, highlighting the nerve’s role in pathogenic signaling. Muscle width remained unchanged, excluding sarcopenia as a confounder. Power analysis confirmed adequate sample size, and most group differences achieved p < 0.01.

Elevations in GFAP-positive astrocytes and Iba-1-positive microglia co-expressing IL-6 within the ventricles signaled neuro-immune activation, providing a plausible substrate for the enduring behavioral deficits observed despite cessation of high-force loading.

Conclusions

To summarize, repetitive reaching tasks in aging female rats triggered a multi-level inflammatory cascade dominated by IL-6, which paralleled the development of lasting pain-like and sickness behaviors. Local musculoskeletal cytokine surges spilled into the bloodstream, traversed the BBB, and engaged limbic circuits implicated in mood and pain processing, linking workplace-style overuse to whole-body malaise.

Taken together, the data point to inflammation as the common thread linking the weakness, hypersensitivity, fatigue, and social withdrawal that many workers report after overuse injuries. Therapies that dampen IL-6 signaling or interrupt this injury-inflammation cycle could accelerate rehabilitation, reduce sick leave, and lower the broader costs of WMSDs.