Cortico-autonomic local arousals and heightened somatosensory arousability during NREM sleep of mice in neuropathic pain

Chronic pain patients frequently suffer from sleep disturbances. Improvement of sleep quality alleviates pain, but neurophysiological mechanisms underlying sleep disturbances require clarification to advance therapeutic strategies. Chronic pain causes high-frequency electrical activity in pain-processing cortical areas that could disrupt the normal process of low-frequency sleep rhythm generation. We found that the spared-nerve-injury (SNI) mouse model, mimicking human neuropathic pain, had preserved sleep-wake behavior. However, when we probed spontaneous arousability based on infraslow continuity-fragility dynamics of non-rapid-eye-movement sleep (NREMS), we found more numerous local cortical arousals accompanied by heart rate increases in hindlimb primary somatosensory, but not in prelimbic, cortices of SNI mice. Closed-loop mechanovibrational stimulation revealed higher sensory arousability in SNI. Sleep in chronic pain thus looked preserved in conventional measures but showed elevated spontaneous and evoked arousability. Our findings develop a novel moment-to-moment probing of NREMS fragility and propose that chronic pain-induced sleep complaints arise from perturbed arousability.