Chen Shuhan, Xie Yanle, Liang Zenghui, Liu Jing, Wang Jingping, Mao Yuanyuan, Xing Fei, Wei Xin, Wang Zhongyu, Yang Jianjun, Yuan Jingjing
Department of Anesthesiology, Perioperative and Pain Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450000, China; Henan Province International Joint Laboratory of Pain, Cognition and Emotion, Zhengzhou, Henan Province 450000, China.
Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine, Harvard Medical School, Boston, MA.
Biomed J. 2025 Jan 2:100826. doi: 10.1016/j.bj.2024.100826.
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.
睡眠对于维持正常生理功能至关重要，而睡眠剥夺与疼痛敏感性增加有关。已知组蛋白去乙酰化酶（HDACs）在调节神经性疼痛中发挥重要作用，但其在睡眠剥夺期间对伤害性超敏反应的影响仍未完全明确。我们采用改良的多平台水环境技术建立睡眠剥夺模型。通过免疫印迹和实时定量PCR检测内侧前额叶皮质（mPFC）中HDAC1/2的表达水平。使用TUNEL检测法确定细胞焦亡的存在。将临床使用的HDAC抑制剂辛二酰苯胺异羟肟酸（SAHA）腹腔注射以抑制HDAC2表达。通过测量 paw withdrawal thresholds（PWTs）和 paw withdrawal latencies（PWLs）评估动物的疼痛行为。我们的研究结果表明，睡眠剥夺会导致伤害性超敏反应增加、mPFC中HDAC2表达上调、核因子红细胞2相关因子2（NRF2）表达下调以及大鼠氧化应激标志物的变化。HDAC抑制剂SAHA通过抑制HDAC2增强了NRF2表达，从而改善了氧化应激并减轻了大鼠的伤害性超敏反应。发现睡眠剥夺大鼠的mPFC组织中细胞凋亡发生率更高，腹腔注射SAHA可降低这种细胞凋亡。将SAHA与NRF2抑制剂ML385共同注射到睡眠剥夺大鼠体内可抵消SAHA的有益作用。总之，HDAC2通过抑制NRF2水平参与氧化应激和细胞凋亡的诱导，从而加剧睡眠剥夺大鼠的伤害性超敏反应。
