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Poor sleep is thought to enhance pain via increasing inflammation. Physical activity is thought to relieve pain via reducing inflammation. This raises two clinical questions: (1) does poor sleep contribute to the transition from acute-to-persistent pain, and (2) does physical activity protect against these sleep-induced effects? We pursued these questions in several studies. We first explored underlying mechanisms in a controlled repetitive overuse injury model (Klyne et al, 2023). Adult female rats performed an intensive repetitive lever-pulling task for 4 weeks to induce symptoms consistent with acute-onset overuse injury, before being divided into three intervention groups (n=8-11/gp by study end) that underwent either voluntary exercise (Ex, running wheel), sleep disturbance (SD), or both (SD+Ex), for 4 weeks after task cessation. Mechanical sensitivity and systemic biomarkers of neuroimmune activity were assessed immediately pre-injury, post-injury and post-intervention. Thus, poor sleep worsened pain behaviors induced by repetitive overuse, paralleled by elevated serum BDNF, and that aerobic exercise ameliorated these changes. We expanded that study to determine if serum biomarkers of inflammation, tissue repair or neuromodulation, may predict or correlate with pain-related behaviors. Sensorimotor behaviors and 70 serum analytes were assayed longitudinally at pre-injury, post-injury, and post-intervention. Grip strength declined significantly after 4 weeks of repetitive lever pulling and recovered with rest in SD and SD+Ex groups, yet improved significantly in Ex group, compared to baseline. Forepaw mechanical sensitivity to monofilament probing was heightened in each group after 4 weeks of task; the Ex with or without SD, ameliorated this sensitivity. Cluster analysis of serum biomarkers identified three clusters with distinct neuroimmune profiles: “low inflammatory” (Cluster 1), “high CINC-1, IFNɣ & IL-1β” (Cluster 2), and “high inflammatory” (Cluster 3). Cluster 3 had higher BDNF and neuropilin-2 than other clusters (all p<0.047), higher TNF than Cluster 2 (p=0.057) and lower TIMP-1 than Cluster 1 (p=0.02). Interestingly, Cluster 3 contained the most SD (78%), one SD+Ex, and no Ex animals, as well as the lowest percent change in grip strength, lowest maximum grip strength, and most lower limb withdrawals to 1 cN and 4 cN probings. Thus, chronic sleep disturbance was associated with a high systemic inflammatory profile and significant declines in sensorimotor behaviors.