Spinal CCL2 Promotes Pain Sensitization by Rapid Enhancement of NMDA-Induced Currents Through the ERK-GluN2B Pathway in Mouse Lamina II Neurons.
Spinal CCL2 Promotes Pain Sensitization by Rapid Enhancement of NMDA-Induced Currents Through the ERK-GluN2B Pathway in Mouse Lamina II Neurons.
复制标题
脊髓 CCL2 通过快速增强小鼠 Lamina II 神经元中的 ERK-GluN2B 途径的 NMDA 诱导电流来促进疼痛敏化
DOI：
10.1007/s12264-020-00557-9
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发表时间：
2020-11
影响因子：
5.6
通讯作者：
Xie RG
中科院分区：
文献类型：
--
作者：
Zhang H;Ma SB;Gao YJ;Xing JL;Xian H;Li ZZ;Shen SN;Wu SX;Luo C;Xie RG
已有研究表明CCL2(C-C基序趋化因子配体2)可诱导慢性疼痛，但其确切机制尚不清楚。在这里，我们建立了模型来探索潜在的机制。行为学实验表明，细胞外信号调节激酶(ERK)的拮抗剂不仅能抑制CCL2诱导的炎性疼痛，还能抑制完全弗氏佐剂引起的疼痛反应。我们提出了涉及到的细胞内信号级联的问题。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，CCR2和ERK的拮抗剂有效地逆转了这一现象。全细胞膜片钳记录显示，CCL2通过激活PERK通路增强NMDAR诱导的电流，该通路可被GluN2B和ERK拮抗剂阻断。综上所述，我们证明了CCL2与CCR2直接相互作用以增强NMDAR诱导的电流，最终主要通过CCL2-CCR2-PERK-GluN2B通路导致炎性疼痛。
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.
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影响因子：
25
作者：
Ji, RR;Baba, H;Woolf, CJ
通讯作者：
Woolf, CJ
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影响因子：
5.3
作者：
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64.5
作者：
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影响因子：
120.1
作者：
Ji, Ru-Rong;Xu, Zhen-Zhong;Gao, Yong-Jing
通讯作者：
Gao, Yong-Jing
影响因子：
3.4
作者：
Lee, KM;Kang, BS;Cho, HJ
通讯作者：
Cho, HJ