• Xiaoyou Shi, Tian-Zhi Guo, Wenwu Li, Peyman Sahbaie, Kenner C Rice, Agnieszka Sulima, J David Clark, and Wade S Kingery.
• From the Anesthesiology Service (X.S., W.L., P.S., J.D.C.) the Palo Alto Veterans Institute of Research (T.-z.G., W.S.K.) Veterans Affairs Palo Alto Health Care System, Palo Alto, California; Department of Anesthesia, Stanford University School of Medicine, Stanford, California (X.S., W.L., P.S., J.D.C.) Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (K.C.R., A.S.).
• Anesthesiology. 2018 Sep 1; 129 (3): 557-575.

What We Already Know About This TopicWHAT 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.MethodsThree 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.ResultsAt 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).ConclusionsDaily exercise reversed nociceptive sensitization, inflammation, anxiety, and memory loss after tibia fracture.

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