Exercise Reverses Nociceptive Sensitization, Upregulated Neuropeptide Signaling, Inflammatory Changes, Anxiety, and Memory Impairment in a Mouse Tibia Fracture Model

Abstract

What We Already Know about This Topic What This Article Tells Us That Is New Background This study tested the hypothesis that ad lib running wheel exercise in a tibia fracture model of complex regional pain syndrome can reverse hindlimb nociceptive sensitization and inflammation in mice. Methods Three weeks after tibia fracture, the cast was removed and hindlimb von Frey thresholds and unweighting were tested; the mice were then randomized to either ad lib access to a running wheel for 4 weeks or no wheel access. After 4 weeks the behavioral testing was repeated and then skin, sciatic nerve, and spinal cord tissues collected for polymerase chain reaction and enzyme immunoassay measurements of neuropeptide and inflammatory mediator levels. A similar protocol was used in fracture mice treated with exercise for 4 weeks, and then the running wheel was removed for 2 weeks. Memory and anxiety were measured in both groups with use of open-field, zero-maze, and novel-objects recognition assays. Results At 7 weeks postfracture the mice with no wheel access exhibited hindlimb allodynia and unweighting, anxiety, memory loss, upregulated spinal neuropeptide signaling, and increased hind paw and spinal inflammatory mediator expression, but the postfracture mice allowed to exercise for 4 weeks exhibited none of these changes (n = 12/cohort). When exercise was stopped for 2 weeks after 4 weeks of running, hindlimb allodynia and unweighting were rekindled, and this nociceptive sensitization was associated with increased sciatic nerve neuropeptide levels and hind paw skin interleukin 6 and nerve growth factor expression (n = 12/cohort). Conclusions Daily exercise reversed nociceptive sensitization, inflammation, anxiety, and memory loss after tibia fracture.

Angiotensin receptor blockade mimics the effect of exercise on recovery after orthopaedic trauma by decreasing pain and improving muscle regeneration

“…2B). As has been reported previously (Shi et al 2018), exercise increased the mechanical threshold ( Fig. 2C).…”

“…In agreement with this theory, we have shown that too early conversion of M1 pro-inflammatory to M2 anti-inflammatory macrophages is detrimental to bone healing because acute inflammation is required for osteogenesis promoted by mesenchymal stem cells and osteoprogenitors . In relation to exercise, in the tibia fracture cast model, we found that it at least transiently reduced cytokine expression in injured limbs (Shi et al 2018) and, furthermore, exercise enhances muscle M2 macrophages (Leung et al 2016). It is therefore possible that too early a resolution of the post-traumatic inflammatory state is actually detrimental to muscle regeneration because of alteration in cytokines, such as interleukin-10, which promote muscle growth and regeneration through immunomodulatory mechanisms (Tidball & Villalta, 2010;Deng et al 2012;Tidball, 2017).…”

“…In relation to exercise, in the tibia fracture cast model, we found that it at least transiently reduced cytokine expression in injured limbs (Shi et al . ) and, furthermore, exercise enhances muscle M2 macrophages (Leung et al . ).…”

“…), decreases allodynia and paw skin pro‐inflammatory cytokines (Shi et al . ), and decreases muscle fibrosis by encouraging extracellular matrix remodelling to promote myofibre growth and repair (Garg & Boppart, ). However, exercise can also enhance pain (Lima et al .…”

“…Exercise is known to improve analgesia and increase pain thresholds in diverse pain conditions, including low back pain, osteoarthritis and myofascial pain (Bement & Sluka, 2016), probably by enhancing central nervous system inhibition and reducing excitation (Fingleton et al 2017). In the periphery, exercise increases release of the anti-inflammatory cytokine interleukin-10 ( Leung et al 2016), decreases allodynia and paw skin pro-inflammatory cytokines (Shi et al 2018), and decreases muscle fibrosis by encouraging extracellular matrix remodelling to promote myofibre growth and repair (Garg & Boppart, 2016). However, exercise can also enhance pain (Lima et al 2017) and the exact timing and mechanism of exercise-induced effects in orthotrauma remains unknown.…”