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外周CCL2通过调节小直径背根神经节神经元的电流来诱导炎性疼痛。

Peripheral CCL2 induces inflammatory pain via regulation of currents in small diameter DRG neurons.

作者信息

Li Lamei, Liu Yuanying, Hu Wenchao, Yang Jing, Ma Suibin, Tian Zhicheng, Cao Zixuan, Pan Kunqing, Jiang Ming, Liu Xia, Wu Shengxi, Luo Ceng, Xie Rou-Gang

机构信息

Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.

School of Life Sciences & Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, Yan'an University, Yan'an, China.

出版信息

Front Mol Neurosci. 2023 Oct 4;16:1144614. doi: 10.3389/fnmol.2023.1144614. eCollection 2023.

DOI:10.3389/fnmol.2023.1144614
PMID:37860084
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10582564/
Abstract

The C-C motif chemokine ligand 2 (CCL2) has been implicated in chronic pain, but its exact mechanism of peripheral sensitization is unknown. In this study, we aimed to clarify the mechanism of CCL2 regulation of ion channels. Our behavioral experiments revealed that ZD7288, a blocker of current, can inhibit CFA and CCL2-mediated mechanical and thermal nociceptive sensitization. Furthermore, patch clamp studies demonstrated that CFA-induced peripheral sensitization primarily affects the excitability of small-diameter DRG neurons. Further studies revealed that inflammatory pain caused by CFA or incubation of DRG with CCL2 mainly affected currents in small-diameter DRG neurons, which were blocked by co-incubation CCR2 antagonist INCB3344 or adenylate cyclase inhibitor SQ22536. Immunohistochemical staining showed that both intraplantar injection of CFA as well as DRG injection of CCL2 resulted in significant upregulation of CCR2/HCN2 expression. In conclusion, we suggest in the inflammatory pain state, CCL2 can act on small-diameter DRG neurons, leading to upregulation of HCN2 expression and consequently , which in turn leads to neuronal hyperexcitability.

摘要

C-C基序趋化因子配体2（CCL2）与慢性疼痛有关，但其外周敏化的确切机制尚不清楚。在本研究中，我们旨在阐明CCL2对离子通道的调节机制。我们的行为学实验表明，ZD7288（一种电流阻滞剂）可以抑制弗氏完全佐剂（CFA）和CCL2介导的机械性和热性伤害性感受敏化。此外，膜片钳研究表明，CFA诱导的外周敏化主要影响小直径背根神经节（DRG）神经元的兴奋性。进一步的研究表明，CFA引起的炎性疼痛或DRG与CCL2共孵育主要影响小直径DRG神经元中的电流，而CCR2拮抗剂INCB3344或腺苷酸环化酶抑制剂SQ22536的共孵育可阻断这些电流。免疫组织化学染色显示，足底注射CFA以及DRG注射CCL2均导致CCR2/HCN2表达显著上调。总之，我们认为在炎性疼痛状态下，CCL2可作用于小直径DRG神经元，导致HCN2表达上调，进而导致神经元兴奋性过高。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/433d1b480234/fnmol-16-1144614-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/339c38d9ed1a/fnmol-16-1144614-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/29875cb87199/fnmol-16-1144614-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/70a73b4879a5/fnmol-16-1144614-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/a0071922bc78/fnmol-16-1144614-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/9ca4bed3c072/fnmol-16-1144614-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/433d1b480234/fnmol-16-1144614-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/339c38d9ed1a/fnmol-16-1144614-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/29875cb87199/fnmol-16-1144614-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/70a73b4879a5/fnmol-16-1144614-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/a0071922bc78/fnmol-16-1144614-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/9ca4bed3c072/fnmol-16-1144614-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b1b/10582564/433d1b480234/fnmol-16-1144614-g006.jpg

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