Minocycline prevents impaired glial glutamate uptake in the spinal sensory synapses of neuropathic rats.
Minocycline prevents impaired glial glutamate uptake in the spinal sensory synapses of neuropathic rats.
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DOI：
10.1016/j.neuroscience.2010.07.049
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发表时间：
2010-10-27
期刊：
影响因子：
3.3
通讯作者：
Weng, H. R.
中科院分区：
文献类型：
--
作者：
Nie, H.;Zhang, H.;Weng, H. R.
脊髓背角中谷氨酸受体和神经胶质细胞的活化是参与各种疼痛病症（包括由外周或中枢神经系统损伤诱导的神经性疼痛）的发病机制的两个基本过程。大量研究表明，米诺环素治疗可减轻由组织炎症或神经损伤诱导的异常性疼痛和痛觉过敏行为。然而，米诺环素预防痛觉过敏的突触机制尚未完全了解。我们最近报道，神经胶质细胞谷氨酸转运蛋白（GT）的谷氨酸摄取不足的关键是增强激活的N-甲基-D-天冬氨酸（NMDA）受体的脊髓感觉突触接受部分坐骨神经结扎（pSNL）。在这项研究中，我们研究了米诺环素如何影响pSNL大鼠脊髓感觉突触中NMDA受体的激活，通过全细胞记录脊髓薄片的脊髓椎板I和II神经元中的NMDA电流。通过免疫组织化学方法分析米诺环素处理对背角胶质细胞GT和星形胶质细胞标志物胶质细胞酸性蛋白（GFAP）表达的影响。我们证明，在脊髓背角的弱和强的外周输入激活的突触中的NMDA受体的正常化激活与pSNL大鼠接受米诺环素腹腔注射的衰减机械异常性疼痛在时间上相关。米诺环素改善pSNL诱导的脊髓背角胶质细胞GT表达下调和星形胶质细胞活化。我们进一步揭示，防止神经胶质细胞谷氨酸摄取不足的突触是至关重要的，在pSNL大鼠与米诺环素治疗的脊髓感觉突触中的NMDA受体的正常激活。我们的研究表明，胶质细胞GT可能是一个潜在的目标，为开发镇痛药。
Activation of glutamate receptors and glial cells in the spinal dorsal horn are two fundamental processes involved in the pathogenesis of various pain conditions, including neuropathic pain induced by injury to the peripheral or central nervous systems. Numerous studies have demonstrated that minocycline treatment attenuates allodynic and hyperalgesic behaviors induced by tissue inflammation or nerve injury. However, the synaptic mechanisms by which minocycline prevents hyperalgesia are not fully understood. We recently reported that deficient glutamate uptake by glial glutamate transporters (GTs) is key for the enhanced activation of N-methyl-D-aspartate (NMDA) receptors in the spinal sensory synapses of rats receiving partial sciatic nerve ligation (pSNL). In this study, we investigated how minocycline affects activation of NMDA receptors in the spinal sensory synapses in rats with pSNL by whole cell recordings of NMDA currents in spinal laminea I and II neurons from spinal slices. The effects of minocycline treatments on the dorsal horn expression of glial GTs and astrocyte marker glial fibrillary acidic protein (GFAP) were analyzed by immunohistochemistry. We demonstrated that normalized activation of NMDA receptors in synapses activated by both weak and strong peripheral input in the spinal dorsal horn is temporally associated with attenuated mechanical allodynia in rats with pSNL receiving intraperitoneal injection of minocycline. Minocycline ameliorated both the downregulation of glial GT expression and the activation of astrocytes induced by pSNL in the spinal dorsal horn. We further revealed that preventing deficient glial glutamate uptake at the synapse is crucial for preserving the normalized activation of NMDA receptors in the spinal sensory synapses in pSNL rats treated with minocycline. Our studies suggest that glial GTs may be a potential target for the development of analgesics.
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