The Role of Neuroinflammation in Complex Regional Pain Syndrome: A Comprehensive Review

Bei Wen,1 Yinbing Pan,2 Jianguo Cheng,3,4 Li Xu,1 Jijun Xu3,5 1Department of Anesthesiology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China; 3Department of Pain Management, Cleveland Clinic, Cleveland, OH, 44195, USA; 4Department of Neuroscience, Cleveland Clinic, Cleveland, OH, 44195, USA; 5Department of Inflammation and Immunity; Cleveland Clinic, Cleveland, OH, 44195, USACorrespondence: Li Xu; Jijun Xu, Email pumchxuli@163.com; xuj3@ccf.orgAbstract: Complex Regional Pain Syndrome (CRPS) is an excess and/or prolonged pain and inflammation condition that follows an injury to a limb. The pathogenesis of CRPS is multifaceted that remains incompletely understood. Neuroinflammation is an inflammatory response in the peripheral and central nervous systems. Dysregulated neuroinflammation plays a crucial role in the initiation and maintenance of pain and nociceptive neuronal sensitization, which may contribute to the transition from acute to chronic pain and the perpetuation of chronic pain in CRPS. The key features of neuroinflammation encompass infiltration and activation of inflammatory cells and the production of inflammatory mediators in both the central and peripheral nervous systems. This article reviews the role of neuroinflammation in the onset and progression of CRPS from six perspectives: neurogenic inflammation, neuropeptides, glial cells, immune cells, cytokines, and keratinocytes. The objective is to provide insights that can inform future research and development of therapeutic targets for CRPS.Keywords: complex regional pain syndrome, neuroinflammation, neurogenic inflammation, glial cells, keratinocytes