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

作　　者：Zi-hua Song Xiang-Jie Song Chen-ling Yang Peng Cao Yu Mao Yan Jin Meng-yun Xu Hai-tao Wang Xia Zhu Wei Wang Zhi Zhang Wen-juan Tao 

机构地区：[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 [2]Innovation Laboratory of Terahertz Biophysics,National Innovation Institute of Defense Technology,Beijing 100071,China [3]Department of Physiology,School of Basic Medical Sciences,Anhui Medical University,Hefei 230022,China [4]College&Hospital of stomatology,Anhui Medical University,Key Lab.of Oral Diseases Research of Anhui Province,Hefei 230022,China [5]Department of Anesthesiology,The First Affiliated Hospital of Anhui Medical University,Hefei 230022,China [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

出　　处：《Acta Pharmacologica Sinica》2023年第7期1337-1349,共13页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(grants 32025017,32121002,81971264,and 32271176);CAS Project for Young Scientists in Basic Research(YSBR-013);Natural Science Foundation of Anhui Province(KJ2020A0138).

摘　　要：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.

关 键 词：diabetic neuropathic pain anterior cingulate cortex MICROGLIA glutamatergic neurons microglia-neuron communication CXCL12/CXCR4 signaling MINOCYCLINE AMD3100 

分 类 号：R589.2[医药卫生—内分泌]