机构：[a]Department of Forensic Medicine, Zhongshan Medical School, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, Guangzhou, China,[b]Department of Anesthesiology, State Key Laboratory of Oncology in Southern China, Sun Yat-Sen Universtiy Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China,临床科室其他部门手术麻醉科华南肿瘤学国家重点实验室中山大学肿瘤防治中心[c]Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-sen University, Sun Yet-Sen University, Guangzhou, China,内科科室普内科中山大学附属第一医院[d]Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
Clinically, Microtubule-targeted agents-induced neuropathic pain hampers chemotherapeutics for patients with cancer. Here, we found that application of paclitaxel or vincristine increased the protein and mRNA expression of CXCL 12 and frequency and amplitude of miniature excitatory post synaptic currents (mEPSCs) in spinal dorsal horn neurons. Spinal local application of CXCL 12 induced the long-term potentiation of nociceptive synaptic transmission and increased the amplitude of mEPSCs. Inhibition of CXCL 12 using the transgenic mice (CXCL 12(-/+)) or neutralizing antibody or siRNA ameliorated the mEPSC's enhancement and mechanical allodynia. In addition, paclitaxel and vincristine both could increase the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the acetylation of histone H4 in the CXCL 12-expressing neurons. Immunoprecipitation and chromatin immunoprecipitation assays demonstrated that antitubulin chemotherapeutics increased the binding of STAT3 to the CXCL 12 gene promoter and the interaction between STAT3 and p300, and contributed to the enhanced transcription of CXCL 12 by increasing the acetylation of histone H4 in CXCL 12 gene promoter. Inhibition of STAT3 by intrathecal injection of adeno-associated virus encoding Cre and green fluorescent protein into STAT3(flox/flox) mice or inhibitor S3I-201 into rats suppressed the CXCL 12 upsurge by decreasing the acetylation of histone H4. Finally, blockade of CXCR4 but not CXCR7 ameliorated the paclitaxel-or vincristine-induced mechanical allodynia. Together, these results suggested that enhanced interaction between STAT3 and p300 mediated the epigenetic upregulation of CXCL 12 in dorsal horn neurons, which contributed to the antitubulin chemotherapeutics-induced persistent pain.
基金：
National Natural Science Foundation of China [31671090, 81271474, 81500948, 81671088, 81600959, 81600957]; Natural Science Foundation of Guangdong [2016A030308003, 2016A030311045]; China Postdoctoral Science Foundation [2016M590833]; Science and Technology Project in Guangzhou [201607010254]; Fundamental Research Funds for the Central Universities [15ykjco4b]
语种：
外文
被引次数：
WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|2 区医学
小类|2 区麻醉学2 区临床神经病学2 区神经科学
最新[2023]版：
大类|1 区医学
小类|1 区临床神经病学1 区神经科学2 区麻醉学
第一作者：
第一作者机构：[a]Department of Forensic Medicine, Zhongshan Medical School, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, Guangzhou, China,
共同第一作者：
通讯作者：
通讯机构：[a]Department of Forensic Medicine, Zhongshan Medical School, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, Guangzhou, China,[d]Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China[*]Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd 2, Guangzhou, China.
医学