A novel co-target of ACY1 governing plasma membrane translocation of SphK1 contributes to inflammatory and neuropathic pain
Baowen Liu,
Wenyao Wu,
LingLing Cui,
Xuemei Zheng,
Ningbo Li,
Xianwei Zhang,
Guangyou Duan
Affiliations
Baowen Liu
Department of Anesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Wenyao Wu
Department of Anesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
LingLing Cui
Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Anesthesiology, Wuhan third Hospital/Tongren Hospital of Wuhan University, Wuhan, Hubei Province, China
Xuemei Zheng
Department of Anesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
Ningbo Li
Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Xianwei Zhang
Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Guangyou Duan
Department of Anesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Corresponding author
Summary: Previous studies validate that inhibiting sodium channel 1.8 (Nav1.8) effectively relieves inflammatory and neuropathic pain. However, Nav1.8 blockers have cardiac side effects in addition to analgesic effects. Here, we constructed a spinal differential protein expression profile using Nav1.8 knockout mice to screen common downstream proteins of Nav1.8 in inflammatory and neuropathic pain. We found that aminoacylase 1 (ACY1) expression was increased in wild-type mice compared to Nav1.8 knockout mice in both pain models. Moreover, spinal ACY1 overexpression induced mechanical allodynia in naive mice, while ACY1 suppression alleviated inflammatory and neuropathic pain. Further, ACY1 could interact with sphingosine kinase 1 and promote its membrane translocation, resulting in sphingosine-1-phosphate upregulation and the activation of glutamatergic neurons and astrocytes. In conclusion, ACY1 acts as a common downstream effector protein of Nav1.8 in inflammatory and neuropathic pain and could be a new and precise therapeutic target for chronic pain.
