Sleep loss differentially reconfigures neural circuits governing pain and neuropsychological homeostasis

Sleep dissipates the physiological load accumulated during wakefulness and restores neural, immune, and endocrine balance to maintain homeostasis. However, how sleep loss disrupts these systems and how recovery sleep (RS) reverses the effects remain poorly understood. Using a mouse model of sleep deprivation (SD), we examined alterations in pain sensitivity, inflammatory responses, pharmacologic responsiveness to opioids and non-benzodiazepine hypnotics, and molecular adaptations across key brain regions. SD heightened nociception, attenuated morphine analgesia and GABA _A receptor-mediated hypnosis, and amplified lipopolysaccharide-evoked inflammation. These effects were accompanied by sustained expression of c-Fos and ΔFosB in multiple brain regions and of Calca in the parabrachial nucleus (PBN), but were largely normalized after RS. Within the hypothalamic arcuate nucleus (ARC), Pomc mRNA expression, unlike Oprm1 , Penk , and Pdyn , was markedly reduced during SD n and restored after RS, paralleling normalization of nociceptive thresholds. Pharmacogenetic activation of ARC-POMC neurons alleviated persistent postoperative pain. In contrast, SD enhanced morphine-induced psychomotor activation linked to dopaminergic transmission, accompanied by sustained c-Fos expression in the ventral tegmental area, nucleus accumbens, and medial prefrontal cortex (mPFC). Notably, this hyperlocomotion persisted despite RS, and was associated with irreversible c-Fos upregulation as well as a sustained, statistically significant elevation of integrated plasticity markers in the mPFC. Together, these findings reveal that sleep loss broadly reconfigures the neural circuits controlling pain, inflammation, and drug responsiveness. While most deficits are reversible with adequate RS, specific dopaminergic and cortical adaptations exhibit incomplete restoration, potentially predisposing patients to chronic, secondary psychopathology.