Chronic random sleep deprivation causes prolonged pain hypersensitivity via the anterior cingulate cortex

Sleep disturbance has a bidirectional relationship with pain. However, the effects of long-term sleep deprivation (SD) and its predictability on nociceptive behavior and neuronal activity remain largely unknown. In this study, we developed two mouse chronic SD models: a random model (RSD), in which mice could not predict when they would be able to sleep, and a fixed-schedule model (FSD). We investigated how these chronic SD patterns alter mechanical sensitivity. In both models, the mechanical threshold markedly decreased during SD, and neuronal activity in the anterior cingulate cortex (ACC) was facilitated. These behavioral and neuronal changes recovered in five weeks after the end of FSD, but persisted after RSD. Chemogenetic inhibition of ACC pyramidal neurons or administration of a chronic pain treatment, mirogabalin, normalized ACC activity, and attenuated the mechanical hypersensitivity in RSD mice. These results suggest that enhanced ACC activity mediates the SD-induced prolonged mechanical hypersensitivity.