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Up-regulation of microglial chemokine CXCL12 in anterior cingulate cortex mediates neuropathic pain in diabetic mice

Acta Pharmacologica Sinica volume 44, pages 1337–1349 (2023)Cite this article

Abstract

Diabetic patients frequently experience neuropathic pain, which currently lacks effective treatments. The mechanisms underlying diabetic neuropathic pain remain unclear. The anterior cingulate cortex (ACC) is well-known to participate in the processing and transformation of pain information derived from internal and external sensory stimulation. Accumulating evidence shows that dysfunction of microglia in the central nervous system contributes to many diseases, including chronic pain and neurodegenerative diseases. In this study, we investigated the role of microglial chemokine CXCL12 and its neuronal receptor CXCR4 in diabetic pain development in a mouse diabetic model established by injection of streptozotocin (STZ). Pain sensitization was assessed by the left hindpaw pain threshold in von Frey filament test. Iba1+ microglia in ACC was examined using combined immunohistochemistry and three-dimensional reconstruction. The activity of glutamatergic neurons in ACC (ACCGlu) was detected by whole-cell recording in ACC slices from STZ mice, in vivo multi-tetrode electrophysiological and fiber photometric recordings. We showed that microglia in ACC was significantly activated and microglial CXCL12 expression was up-regulated at the 7-th week post-injection, resulting in hyperactivity of ACCGlu and pain sensitization. Pharmacological inhibition of microglia or blockade of CXCR4 in ACC by infusing minocycline or AMD3100 significantly alleviated diabetic pain through preventing ACCGlu hyperactivity in STZ mice. In addition, inhibition of microglia by infusing minocycline markedly decreased STZ-induced upregulation of microglial CXCL12. Together, this study demonstrated that microglia-mediated ACCGlu hyperactivity drives the development of diabetic pain via the CXCL12/CXCR4 signaling, thus revealing viable therapeutic targets for the treatment of diabetic pain.

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Fig. 1: Microglia are activated in STZ 7W mice.
Fig. 2: Effects of ACC infusion of minocycline on pain behaviors.
Fig. 3: ACCGlu neuronal activity is enhanced in STZ 7W mice.
Fig. 4: The expression of microglial CXCL12 is increased in STZ 7W mice.
Fig. 5: Inhibition of CXCR4 alleviates STZ 7W-induced pain sensitization.
Fig. 6: CXCL12 reduced neuronal CXCR4 in the ACC.

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All data necessary to understand and assess the conclusions of this study are available in the main text or the supplementary materials. There are no restrictions on data availability in the manuscript.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grants 32025017, 32121002, 81971264, and 32271176), CAS Project for Young Scientists in Basic Research (YSBR-013), and Natural Science Foundation of Anhui Province (KJ2020A0138).

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  1. These authors contributed equally: Zi-hua Song, Xiang-jie Song

Authors and Affiliations

  1. Department of Anesthesiology, The First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China

    Zi-hua Song, Xiang-Jie Song, Peng Cao, Yu Mao, Yan Jin, Meng-yun Xu, Hai-tao Wang, Xia Zhu & Zhi Zhang

  2. Innovation Laboratory of Terahertz Biophysics, National Innovation Institute of Defense Technology, Beijing, 100071, China

    Zi-hua Song

  3. Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230022, China

    Chen-ling Yang & Wen-juan Tao

  4. College & Hospital of stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei, 230022, China

    Chen-ling Yang & Wen-juan Tao

  5. Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Yu Mao

  6. Department of Endocrinology and Laboratory for Diabetes, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China

    Meng-yun Xu & Wei Wang

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Contributions

ZHS and XJS designed the studies, conducted most of the experiments and data analysis, and wrote the draft manuscript. PC, CLY, YM, and YJ conducted the behavioral experiments and data analyses and wrote the text of the final manuscript. MYX, WW, HTW, and XZ conducted some of the molecular and behavioral experiments. WJT, and ZZ were involved in the overall design of the study and the revision of the final manuscript. ZZ and WJT were involved in the overall design of the project, individual experiments, data analysis, and the writing of the final manuscript.

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Correspondence to Wei Wang, Zhi Zhang or Wen-juan Tao.

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Song, Zh., Song, XJ., Yang, Cl. et al. Up-regulation of microglial chemokine CXCL12 in anterior cingulate cortex mediates neuropathic pain in diabetic mice. Acta Pharmacol Sin 44, 1337–1349 (2023). https://doi.org/10.1038/s41401-022-01046-7

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