Sphingosine-1 phosphate receptor 1 contributes to central sensitization in recurrent nitroglycerin-induced chronic migraine model
作者全名："Pan, Qi; Wang, Yunfeng; Tian, Ruimin; Wen, Qianwen; Qin, Guangcheng; Zhang, Dunke; Chen, Lixue; Zhang, Yixin; Zhou, Jiying"
作者地址："[Pan, Qi; Wang, Yunfeng; Tian, Ruimin; Zhang, Yixin; Zhou, Jiying] Chongqing Med Univ, Dept Neurol, Affiliated Hosp 1, 1st You Yi Rd, Chongqing 400016, Peoples R China; [Wang, Yunfeng] North Sichuan Med Coll, Clin Med Coll 2, Nanchong Cent Hosp, Dept Neurol, Nanchong, Peoples R China; [Wen, Qianwen; Qin, Guangcheng; Zhang, Dunke; Chen, Lixue] Chongqing Med Univ, Lab Res Ctr, Affiliated Hosp 1, Chongqing, Peoples R China"
通信作者："Zhang, YX; Zhou, JY (通讯作者)，Chongqing Med Univ, Dept Neurol, Affiliated Hosp 1, 1st You Yi Rd, Chongqing 400016, Peoples R China."
来源：JOURNAL OF HEADACHE AND PAIN
ESI学科分类：NEUROSCIENCE & BEHAVIOR
关键词：Chronic migraine; Central sensitization; S1PR1; Microglia; STAT3
摘要："Background Central sensitization is an important pathophysiological mechanism of chronic migraine (CM), and microglia activation in trigeminocervical complex (TCC) contributes to the development of central sensitization. Emerging evidence implicates that blocking sphingosine-1-phosphate receptor 1 (S1PR1) can relieve the development of chronic pain and inhibit the activation of microglia. However, it is unclear whether S1PR1 is involved in the central sensitization of CM. Therefore, the purpose of this study is to explore the role of S1PR1 and its downstream signal transducers and activators of transcription 3 (STAT3) signaling pathway in the CM, mainly in inflammation. Methods Chronic intermittent intraperitoneal injection of nitroglycerin (NTG) established a mouse model of CM. First, we observed the changes and subcellular localization of S1PR1 in the trigeminocervical complex (TCC). Then, W146, a S1PR1 antagonist; SEW2871, a S1PR1 agonist; AG490, a STAT3 inhibitor were applied by intraperitoneal injection to investigate the related molecular mechanism. The changes in the number of microglia and the expression of calcitonin gene-related peptide (CGRP) and c-fos in the TCC site were explored by immunofluorescence. In addition, we studied the effect of S1PR1 inhibitors on STAT3 in lipopolysaccharide-treated BV-2 microglia. Results Our results showed that the expression of S1PR1 was increased after NTG injection and S1PR1 was colocalized with in neurons and glial cells in the TCC. The S1PR1 antagonist W146 alleviated NTG-induced hyperalgesia and suppressed the upregulation of CGRP, c-fos and pSTAT3 in the TCC. Importantly, blocking S1PR1 reduced activation of microglia. In addition, we found that inhibiting STAT3 signal also attenuated NTG-induced basal mechanical and thermal hyperalgesia. Conclusions Our results indicate that inhibiting S1PR1 signal could alleviate central sensitization and inhibit microglia activity caused by chronic NTG administration via STAT3 signal pathway, which provide a new clue for the clinical treatment of CM."
基金机构："National Natural Science Foundation of China [81971063, 82101296]; Cultivation Fund of The First Affiliated Hospital of Chongqing Medical University [ZYRC2020-01]"
基金资助正文："This work was supported by the National Natural Science Foundation of China (No: 81971063, No: 82101296) and the Cultivation Fund of The First Affiliated Hospital of Chongqing Medical University (NO: ZYRC2020-01)."