Spinal CCL2 Promotes Pain Sensitization by Rapid Enhancement of NMDA-Induced Currents Through the ERK-GluN2B Pathway in Mouse Lamina II Neurons
Hui Zhang 1,2 • Sui-Bin Ma1 • Yong-Jing Gao3 • Jun-Ling Xing4 • Hang Xian1,5 • Zhen-Zhen Li 1 • Shu-Ning Shen 1,6 • Sheng-Xi Wu 1 • Ceng Luo 1 • Rou-Gang Xie 1
1 Department of Neurobiology, Fourth Military Medical University, Xi’an 710032, China
2 Department of Health Statistics, Fourth Military Medical University, Xi’an 710032, China
3 Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key laboratory of Neuroregeneration, Nantong University, Nantong 226001, China
4 Department of Radiation Biology, Faculty of Preventive Medicine, Fourth Military Medical University, Xi’an 710032, China
5 Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
6 Department of Stomatology, No. 984 Hospital of the People’s Liberation Army, Beijing 100094, China
Abstract
Previous studies have shown that CCL2 (C–C motif chemokine ligand 2) induces chronic pain, but the exact mechanisms are still unknown. Here, we established models to explore the potential mechanisms. Behavioral experiments revealed that an antagonist of extracellular signal-regulated kinase (ERK) inhibited not only CCL2-induced inflammatory pain, but also pain responses induced by complete Freund’s adjuvant. We posed the question of the intracellular signaling cascade involved. Subsequent experiments showed that CCL2 up-regulated the expression of phosphorylated ERK (pERK) and N-methyl D-aspartate receptor [NMDAR] subtype 2B (GluN2B); meanwhile, antagonists of CCR2 and ERK effectively reversed these phenomena. Whole-cell patch-clamp recordings revealed that CCL2 enhanced the NMDAR-induced currents via activating the pERK pathway, which was blocked by antagonists of GluN2B and ERK. In summary, we demonstrate that CCL2 directly interacts with CCR2 to enhance NMDAR-induced currents, eventually leading to inflammatory pain mainly through the CCL2–CCR2–pERK–GluN2B pathway.
Keywords
C-C motif chemokine ligand 2; Monocyte chemoattractant protein 1; Neuron-glial interaction; Extracellular signal-regulated kinase
