Chronic restraint stress induces abnormal behaviors in pain sensitivity and cognitive function in mice: the role of Keap1/Nrf2 pathway

Abstract

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.

Keywords:

• Acute restraint stress
• chronic restraint stress
• pain sensitivity
• cognitive dysfunction
• Keap1
• Nrf2

Author contributions

NY: conceptualization; methodology; formal analysis; investigation; software; writing-original draft; visualization. YW: formal analysis; investigation; software; writing-original draft. XXL: conceptualization; writing-review and editing; supervision. GFZ: conceptualization; investigation; visualization; writing-review and editing; supervision; funding acquisition.

Disclosure statement

All the authors declared no conflict of interest.

Additional information

Funding

This project was supported by National Natural Science Foundation of China (Grant nos. 82201345).

Notes on contributors

Ning Yang

Ning Yang received an M.S. degree in Anesthesiology from Huazhong University of Science and Technology in 2019, and a B.S. degree in Anesthesiology from Shanxi Medical College in 2016. Currently, he works as a resident physician in the Anesthesiology Department of Union Hospital in Wuhan, China. Her professional interests lie in the mechanism of stress-induced behavior.

Yue Wang

Yue Wang received a Ph.D. degree in Anesthesiology from Huazhong University of Science and Technology in 2023, and a B.S. degree in clinical medicine from Zhengzhou University in 2018. Currently, she works as a resident physician at the Fujian Medical College in Fuzhou, China. Her professional interests lie in perioperative brain protection.

Xiaoxiao Luo

Xiaoxiao Luo received a Ph.D. degree in Oncology, and a B.S. degree in clinical medicine from Huazhong University of Science and Technology. Currently, she works as an attending physician in the oncology Department of Tongji Hospital in Wuhan, China.

Gaofeng Zhan

Gaofeng Zhan received a Ph.D. degree in Anesthesiology from Huazhong University of Science and Technology in 2021, and a B.S. degree in clinical medicine from Nanchang University in 2016. Currently, he works as an attending physician in the Anesthesiology Department of Tongji Hospital in Wuhan, China. His professional interests lie in perioperative brain protection.