Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Anesthesiology, Fujian Medical University Union Hospital, Fuzhou, China.
Stress. 2024 Jan;27(1):2316050. doi: 10.1080/10253890.2024.2316050. Epub 2024 Feb 20.
Stress is a series of physical and psychological responses to external and internal environmental stimuli. Growing studies have demonstrated the detrimental impacts of acute restraint stress (ARS) and chronic restraint stress (CRS) on animal behavior. However, the related pathogenesis and therapeutic mechanisms remain unclear. Hence, the present study aimed to examine whether unfolded protein response (UPR) and Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 related factor 2 (Nrf2) pathway are associated with ARS- and CRS- induced abnormal behaviors of pain sensitivity and cognitive function. We here used four behavioral tests to evaluate pain sensitivity and cognitive function in ARS and CRS mice. CRS markedly decreased Paw Withdrawal Mechanical Threshold (PWMT) and Tail-flick Latency (TFL) scores, whereas ARS altered TFL but had no effect on PWMT scores. Additionally, CRS, but not ARS, significantly changed behaviors in nest building behavior and MWMT. Intriguingly, the expression of Keap1 and Nrf2 protein were decreased in the spinal cord and hippocampus in CRS mice, but not in ARS mice. Moreover, neither the ARS nor the CRS groups significantly differed from the control group in terms of endoplasmic reticulum stress (ERS). Taken together, this study demonstrated that CRS could induce abnormal pain sensitivity and cognitive function probably via Keap1/Nrf2 pathway in spinal cord and hippocampus. It is therefore likely that effective intervention of Keap1/Nrf2 pathway may contribute to preventing and treating hyperalgesia and cognitive dysfunction in CRS.
应激是机体对外界和内部环境刺激产生的一系列生理和心理反应。越来越多的研究表明，急性束缚应激（ARS）和慢性束缚应激（CRS）对动物行为有不良影响。然而，其相关发病机制和治疗机制尚不清楚。因此，本研究旨在探讨未折叠蛋白反应（UPR）和 Kelch 样 ECH 相关蛋白 1（Keap1）-核因子红细胞 2 相关因子 2（Nrf2）通路是否与 ARS 和 CRS 引起的疼痛敏感性和认知功能异常行为有关。我们使用了四种行为测试来评估 ARS 和 CRS 小鼠的疼痛敏感性和认知功能。CRS 显著降低了 Paw Withdrawal Mechanical Threshold（PWMT）和 Tail-flick Latency（TFL）评分，而 ARS 改变了 TFL 但对 PWMT 评分没有影响。此外，CRS 而非 ARS 显著改变了筑巢行为和 MWMT 行为。有趣的是，CRS 小鼠脊髓和海马中的 Keap1 和 Nrf2 蛋白表达降低，但 ARS 小鼠则没有。此外，无论是 ARS 还是 CRS 组，内质网应激（ERS）与对照组相比均无显著差异。综上所述，本研究表明，CRS 可能通过脊髓和海马中的 Keap1/Nrf2 通路引起异常的疼痛敏感性和认知功能。因此，有效干预 Keap1/Nrf2 通路可能有助于预防和治疗 CRS 中的痛觉过敏和认知功能障碍。
