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

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Abstract

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 expression 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 pathological pain.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (31400949, 81502102, 31471059, 81371498, and 31371121) and NIH R01, USA Grants (DE17794, DE22743, and NS87988).

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Authors and Affiliations

  1. Department of Neurobiology and Collaborative Innovation Center for Brain Science, The Fourth Military Medical University, Xi’an, 710032, China

    Rou-Gang Xie, Ceng Luo, Wen-Ting Wang & Sheng-Xi Wu

  2. Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA

    Rou-Gang Xie & Ru-Rong Ji

  3. Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key laboratory of Neuroregeneration, Nantong University, Nantong, 226001, China

    Yong-Jing Gao

  4. Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea

    Chul-Kyu Park

  5. Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China

    Ning Lu

  6. Department of Neurobiology, Duke University Medical Center, Durham, NC, 27710, USA

    Ru-Rong Ji

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  1. Rou-Gang Xie
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Xie, RG., Gao, YJ., Park, CK. et al. Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation, and Inflammatory Pain via CCR2: Further Insights into Molecular, Synaptic, and Cellular Mechanisms. Neurosci. Bull. 34, 13–21 (2018). https://doi.org/10.1007/s12264-017-0106-5

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