Overuse Injury Induces Persistent Behavioral Declines That Correlate with Higher IL-6 Expression in the Affected Musculoskeletal Tissues, Circulation and Brain

Mary F Barbe^1*Alex G Lambi²Michele Y Harris¹Parth R Patel¹Istvan P Tamas¹Elizabeth R Mcgonagle¹Megan Van Der Bas¹Betsy A Kalicharan¹Lewis Holt-Bright¹Steven N Popoff¹David Murray Klyne^3*

• ¹Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
• ²University of New Mexico, Albuquerque, New Mexico, United States
• ³The University of Queensland, Brisbane, Queensland, Australia

Background: Pain and sickness behaviors can be elicited by systemic inflammation. We sought to determine if mature rats displayed these behaviors following overuse injury, and whether they correlated with inflammatory cytokines in musculoskeletal tissues, circulation, and brain. Methods: Mature female Sprague-Dawley rats were used: 26 Controls and 41 rats trained across 6 weeks to pull at high force levels. Following training, 28 performed a high repetition low force task for 6 more weeks (Task); the remaining rested (Trained+Rest). Behavioral data was collected at baseline, following training, and at study end. Tissues and serum were then collected and examined for inflammatory cytokines.Results: Following training, Task and Trained+Rest rats exhibited grip strength declines and forepaw sensitivity, compared to baseline and Controls. Following task or rest, these behavioral changes persisted in addition to a reduction in social interactions (with juvenile female rats) in Task rats, whereas Trained+Rest rats exhibited only low grip strength. Pro-inflammatory cytokines were elevated in serum and forelimb musculoskeletal and nerve tissues in Task relative to Control rats; IL-6 was elevated in serum and tissues in Task relative to Trained+Rest rats. IL-6 immunostaining was observed in brain ependymal cells and cingulate cortex of Task and Trained+Rest rats relative to Control rats, and one circumferential blood brain region of Task rats relative to the other groups. Higher cytokine levels in tissues often correlated with poorer behavioral responses.Conclusions: These data indicate that overuse injury induces inflammatory responses within the local/damaged tissues, circulation and brain that drives pain-related and sickness behaviors.