title: Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation, and Inflammatory Pain via CCR2: Further Insights into Molecular, Synaptic, and Cellular Mechanisms.
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.
authors.affiliation: Department of Neurobiology and Collaborative Innovation Center for Brain Science, The Fourth Military Medical University, Xi'an, 710032, China. rgxie@fmmu.edu.cn.|Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA. rgxie@fmmu.edu.cn.
authors.forename: Rou-Gang
authors.initials: RG
authors.lastname: Xie
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key laboratory of Neuroregeneration, Nantong University, Nantong, 226001, China.
authors.forename: Yong-Jing
authors.initials: YJ
authors.lastname: Gao
authors.affiliation: Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea.
authors.forename: Chul-Kyu
authors.initials: CK
authors.lastname: Park
authors.affiliation: Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Lu
authors.affiliation: Department of Neurobiology and Collaborative Innovation Center for Brain Science, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Ceng
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Neurobiology and Collaborative Innovation Center for Brain Science, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Wang
authors.affiliation: Department of Neurobiology and Collaborative Innovation Center for Brain Science, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Sheng-Xi
authors.initials: SX
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA. ru-rong.ji@duke.edu.|Department of Neurobiology, Duke University Medical Center, Durham, NC, 27710, USA. ru-rong.ji@duke.edu.
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009187:Myelitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D059408:Pain Management; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048588:Benzoxazines; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018683:Excitatory Amino Acid Agents; D018690:Excitatory Amino Acid Agonists; D008164:Luminescent Proteins; C579117:RS 504393; C493477:Slc17a6 protein, mouse; D013141:Spiro Compounds; D050599:Vesicular Glutamate Transport Protein 2; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D013004:Somatostatin; D005620:Freund's Adjuvant
keywords: Chemokines; C–C motif chemokine ligand 2 (CCL2); Monocyte chemoattractant protein 1 (MCP-1); Neuron–glial interaction