1Department of Neurobiology and Collaborative Innovation Center for Brain Science, The Fourth Military Medical University, Xi’an 710032, China
2Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA
3Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key laboratory of Neuroregeneration, Nantong University, Nantong 226001, China
4Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea
5Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China
6Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA

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.

Keywords

Chemokines, C–C motif chemokine ligand 2 (CCL2), Monocyte chemoattractant protein 1 (MCP-1), Neuron–glial interaction

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