Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation, and Inflammatory Pain via CCR2： Further Insights into Molecular, Synaptic, and Cellular Mechanisms

作     者：Rou-Gang Xie Yong-Jing Gao Chul-Kyu Park Ning Lu Ceng Luo Wen-Ting Wang Sheng-Xi Wu Ru-Rong Ji 

作者机构：Department of Neurobiology and Collaborative Innovation Center for Brain Science The Fourth Military Medical University Xi'an 710032 China Department of Anesthesiology Duke University Medical Center Durham NC 27710 USA Pain Research Laboratory Institute of Nautical Medicine Jiangsu Key laboratory of Neuroregeneration Nantong University Nantong 226001 China Department of Physiology College of Medicine Gachon University Incheon 21999 Republic of Korea Institutes of Brain Science and State Key Laboratory of Medical Neurobiology Collaborative Innovation Center for Brain Science Fudan University Shanghai 200032 China Department of Neurobiology Duke University Medical Center Durham NC 27710 USA 

出 版 物：《Neuroscience Bulletin》 (神经科学通报（英文版）)

年 卷 期：2018年第34卷第1期

页      面：13-21页

核心收录：

学科分类：0710[理学-生物学] 1006[医学-中西医结合] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 100602[医学-中西医结合临床] 

基　　金：supported by grants from the National Natural Science Foundation of China(31400949,81502102,31471059,81371498,and 31371121) NIH R01,USA Grants(DE17794,DE22743,and NS87988) 

主　　题：Chemokines C-C motif chemokine ligand 2 (CCL2) Monocyte chemoattractant protein 1 (MCP-1) Neuron-glial interaction 

摘      要：Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown to enhance N-methyl-D-aspartate （NMDA）-induced currents in spinal outer lamina II （Iio） neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expres- sion in excitatory vesicular glutamate transporter subtype 2-positive （VGLUT2＋） neurons. CCL2 increased NMDA- induced currents in CCR2＋/VGLUT2＋ neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin- expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2- expressing excitatory neurons in spinal lamina Iio, and this underlies the generation of central sensitization in patho- logical pain.