Zong-Qi Huang,1 Xiao-Qin Li,1 Yin-Di Wang,2 Jia-Yi Li,2 Yu-He Tian,1 Yong-Min Liu,2,* Jun-Qiang Si1,3,4,* 

1Department of Physiology, Shihezi University Medical College, Shihezi, 832000, People’s Republic of China; 2Department of Neurology, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, People’s Republic of China; 3The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University Medical College, Shihezi, 832000, People’s Republic of China; 4Department of Physiology, Huazhong University of Science and Technology of Basic Medical Sciences, Wuhan, 430070, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jun-Qiang Si, Email sijunqiang@shzu.edu.cn Yong-Min Liu, Email 335980327@qq.com

Abstract: Pain is a common symptom of many diseases and seriously affects the quality of life. Circadian rhythm is the regular, cyclical physiological, biochemical, and behavioral changes that occur within a 24-hour period in biological organisms, primarily regulated by clock genes. Pain sensitivity may have circadian rhythms, with clock genes likely influencing this pain-related rhythmicity. Therefore, restoring normal circadian rhythms and regulating the expression of clock genes are regarded as viable strategies to combat the development of pain. First, this review elucidates the core operational mechanisms of clock genes. Second, it also discusses the relationship among multiple types of pain and clock genes, such as sciatic nerve injury, inflammatory pain, chemotherapy-induced neuropathic pain, headache, the pain of Restless Legs Syndrome and fibromyalgia. Third, it presents the pain treatment and pain management strategies based on the current research on circadian rhythms. Exploring the role of circadian rhythm in pain can help increase our understanding of pain and have significant clinical implications for pain patients.
Plain Language Summary: The core of the circadian rhythm is driven by genes such as Per, Cry, Bmal1, Clock, Npas2 and Rev-erbα, and abnormal expression of these genes is directly associated with sciatic nerve injury, inflammatory pain, chemotherapy-induced neuropathic pain, headache, the pain of Restless Legs Syndrome and fibromyalgia.
This study focuses on the mechanisms of the circadian rhythm, the relationship between clock genes and pain, as well as the applications of the circadian rhythm in pain management and treatment.
Pain can be alleviated through chronotherapy, clock gene-based therapies and Traditional Chinese Medicine to regulate clock genes and suppress inflammatory factors. Future research on circadian rhythms and pain may provide more comprehensive solutions for pain management and treatment.

Keywords: clock genes, pain management, the core mechanism of circadian rhythm, chronotherapy