Sleep deprivation affects pain sensitivity by increasing oxidative stress and apoptosis in the medial prefrontal cortex of rats via the HDAC2-NRF2 pathway.

Abstract

Sleep is crucial for sustaining normal physiological functions, and sleep deprivation has been associated with increased pain sensitivity. The histone deacetylases (HDACs) are known to significantly regulate in regulating neuropathic pain, but their involvement in nociceptive hypersensitivity during sleep deprivation is still not fully understood. Utilizing a modified multi-platform water environment technique to establish a sleep deprivation model. We measured the expression levels of HDAC1/2 in the medial prefrontal cortex (mPFC) through immunoblotting and real-time quantitative PCR. The presence of pyroptosis was determined using a TUNEL assay. Suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor employed clinically, was injected into the peritoneal cavity to inhibit HDAC2 expression. Animal pain behaviors were evaluated by measuring paw withdrawal thresholds (PWTs) and paw withdrawal latencies (PWLs). Our findings indicate that sleep deprivation leads to increased nociceptive hypersensitivity, an upregulation of HDAC2 expression in the mPFC, a downregulation of the expression of nuclear factor erythroid 2-related factor 2 (NRF2), and changes in markers of oxidative stress in rats. SAHA, the HDAC inhibitor, enhanced NRF2 expression by inhibiting HDAC2, which consequently ameliorated oxidative stress and mitigated nociceptive hypersensitivity in rats. The incidence of apoptosis was found to be higher in the mPFC tissues of sleep deprivation rats, and the intraperitoneal administration of SAHA decreased this apoptosis. The co-injection of SAHA and the NRF2 inhibitor ML385 into sleep deprivation rats negated the beneficial effects of SAHA. In conclusion, HDAC2 is implicated in the induction of oxidative stress and apoptosis by suppressing NRF2 levels, thereby exacerbating nociceptive hypersensitivity in sleep deprivation rats.