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.
Innovation Laboratory of Terahertz Biophysics, National Innovation Institute of Defense Technology, Beijing, 100071, China.
Acta Pharmacol Sin. 2023 Jul;44(7):1337-1349. doi: 10.1038/s41401-022-01046-7. Epub 2023 Jan 25.
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 (ACC) 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 ACC and pain sensitization. Pharmacological inhibition of microglia or blockade of CXCR4 in ACC by infusing minocycline or AMD3100 significantly alleviated diabetic pain through preventing ACC 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 ACC hyperactivity drives the development of diabetic pain via the CXCL12/CXCR4 signaling, thus revealing viable therapeutic targets for the treatment of diabetic pain.
糖尿病患者经常会经历神经性疼痛，而目前这种疼痛缺乏有效的治疗方法。糖尿病神经性疼痛的发病机制尚不清楚。已知前扣带皮层（ACC）参与来自内外感觉刺激的疼痛信息的处理和转换。越来越多的证据表明，中枢神经系统中小胶质细胞的功能障碍与许多疾病有关，包括慢性疼痛和神经退行性疾病。在这项研究中，我们通过注射链脲佐菌素（STZ）建立了一个糖尿病小鼠模型，研究了小胶质细胞趋化因子 CXCL12 及其神经元受体 CXCR4 在糖尿病疼痛发展中的作用。通过 von Frey 细丝试验评估左后爪痛阈来评估痛觉过敏。使用免疫组织化学和三维重建相结合的方法检测 ACC 中的 Iba1 小胶质细胞。通过来自 STZ 小鼠的 ACC 切片中的全细胞膜片钳记录、体内多电极电生理和光纤光度记录检测 ACC 中谷氨酸能神经元的活性。我们发现，注射后第 7 周时，ACC 中的小胶质细胞明显被激活，小胶质细胞 CXCL12 的表达上调，导致 ACC 过度活跃和痛觉过敏。在 ACC 中用米诺环素或 AMD3100 抑制小胶质细胞或阻断 CXCR4 可通过防止 STZ 小鼠的 ACC 过度活跃而显著缓解糖尿病疼痛。此外，用米诺环素抑制小胶质细胞可显著降低 STZ 诱导的小胶质细胞 CXCL12 的上调。总之，这项研究表明，小胶质细胞介导的 ACC 过度活跃通过 CXCL12/CXCR4 信号通路驱动糖尿病疼痛的发展，从而为治疗糖尿病疼痛提供了可行的治疗靶点。
