Zhang Hui, Ma Sui-Bin, Gao Yong-Jing, Xing Jun-Ling, Xian Hang, Li Zhen-Zhen, Shen Shu-Ning, Wu Sheng-Xi, Luo Ceng, Xie Rou-Gang
Department of Neurobiology, Fourth Military Medical University, Xi'an, 710032, China.
Department of Health Statistics, Fourth Military Medical University, Xi'an, 710032, China.
Neurosci Bull. 2020 Nov;36(11):1344-1354. doi: 10.1007/s12264-020-00557-9. Epub 2020 Aug 18.
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.
先前的研究表明，CCL2（C-C基序趋化因子配体2）可诱发慢性疼痛，但其确切机制仍不清楚。在此，我们建立模型以探究潜在机制。行为学实验显示，细胞外信号调节激酶（ERK）拮抗剂不仅抑制CCL2诱导的炎性疼痛，还抑制弗氏完全佐剂诱导的疼痛反应。我们提出了所涉及的细胞内信号级联反应的问题。随后的实验表明，CCL2上调磷酸化ERK（pERK）和N-甲基-D-天冬氨酸受体[NMDAR]2B亚型（GluN2B）的表达；同时，CCR2和ERK拮抗剂有效逆转了这些现象。全细胞膜片钳记录显示，CCL2通过激活pERK途径增强NMDAR诱导的电流，这一作用被GluN2B和ERK拮抗剂阻断。总之，我们证明CCL2直接与CCR2相互作用以增强NMDAR诱导的电流，最终主要通过CCL2-CCR2-pERK-GluN2B途径导致炎性疼痛。
