Neuroimmune pathways linking sleep disturbance to persistent pain after injury are mitigated by exercise

ABSTRACT: Sleep and physical activity are modifiable behaviours linked to pain. Sleep disturbance often co-occurs with persistent pain and may contribute to its development. Exercise is a first-line treatment for chronic pain. Previous work showed that sleep disturbance worsens and prolongs postinjury pain behaviours, exercise mitigates these effects, and brain-derived neurotrophic factor may play a mechanistic role. Deeper insight requires a broader assessment of pain behaviours and systemic biomarkers related to inflammation, tissue repair, and neuromodulation. This study addresses these gaps. Twenty-nine adult female Sprague-Dawley rats performed an intensive lever-pulling task for 4 weeks to induce overuse injury and then underwent one of three 4-week interventions: intermittent sleep disturbance, voluntary exercise (via access to a running wheel), or both. Pain-related behaviours and 71 blood analytes were measured immediately preinjury, postinjury, and postintervention. Overuse injury decreased grip strength and increased mechanical sensitivity in the injured forepaws. After cessation of the injury inducing task, these changes persisted with sleep disturbance but recovered to, or exceeded, preinjury levels with exercise, even with concurrent sleep disturbance. Biomarker analyses revealed distinct neuroimmune responses to injury and sleep disturbance, particularly mediators of inflammation and neuroplasticity, that were offset by exercise. Correlations between biomarkers and behavioural outcomes support mechanistic links between injury, sleep, exercise, and recovery. Findings demonstrate that postinjury sleep disturbance induces neuroimmune changes that increase persistent pain vulnerability, whereas aerobic exercise counters these effects. This highlights the interaction between sleep and exercise in recovery and their potential as strategies to prevent and manage chronic pain.