Roles of spinal astrocyte in the induction and maintenance of chronic pain

脊髓星形胶质细胞在慢性疼痛的诱导和维持中的作用

• 批准号: 18613006
• 负责人: NAKAGAWA Takayuki
• 金额: $ 2.62万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18613006/
• 关键词: chronic pain; astrocyte; ATP; MAPK; glial glutamate transporter; GLT-1; trafficking; spinal cord; 中枢神経感作; グルタミン酸トランスポーター; 遺伝子導入; グルタミン酸; ERK; 組換えアデノウイルス

We have investigated the roles of spinal astrocytes in chronic pain. Intrathecal administration of ATP to rats produced short-lasting hyperalgesia (<20 min) and subsequently long-lasting allodynia, which appeared within 5 min, reached a plateau between 15 and 30min and lasted fm 3-4 weeks. In the spinal cord, intrathecal ATP administration caused microglia activation within 1 day (induction phase) and subsequently astrocytic activation, which peaked at 1-3 days (transition and early maintenance phase). Taken together with further behavioral studies using inhibitors for microglial and astrocytic activation, and MAPK inhibitors, it is suggested that early microglia activation contributes to the initial induction of chronic pain and precipitates, in turn, the subsequent and sustained astrocytic activation, which is implicated in the transition and maintenance of the persistent pain state.In the inflammatory (carrageenan/kaolin) and neuropathic pain (partial sciatic nerve ligation (pSNL)) … More rat models, the total expression or membrane localization of a glial glutamate transporter GLT-1, which is mainly expressed in astrocytes, in the spinal cord was decreased. Gene transfer of GLT-1 into the spinal cord by the recombinant adenoviruses reduced the induction of inflammatory mechanical hyperalgesia and pSNL-induced allodynia (neuropathic pain), although it had no effect in acute mechanical and thermal pain. These results suggest that dysfunction of GLT-1 by decreased expression of intracellular trafficking in astrocytes contributes to the induction of chronic pain.Finally, to elucidate the molecular mechanisms underlying GLT-1 trafficking in astrocyte, we constructed a recombinant adenovirus expressing EGFP-tagged GLT-1 and analyzed time-lapse imaging of GLT-1 dynamics in live astrocytes. In rat astroglia-neuronal mixed cultures, treatment with glutamate rapidly induced formation of clusters and intracellular trafficking of GLT-1 via endocytotic pathways. Furthermore, our results suggest that Na^+ influx associated with substrate-transport via GLT-1, but not stimulation of glutamate receptors and intracellular Ca^<2+> signaling, triggers the GLT-1 clustering. Less

我们已经研究了脊髓星形胶质细胞在慢性疼痛中的作用。鞘内给大鼠的ATP给药产生了短暂的痛觉过敏（<20分钟），随后出现在5分钟内的持久性异常症，在15至30分钟之间达到了高原，持续了FM 3-4周。在脊髓中，鞘内ATP给药会在1天（诱导阶段）和随后的星形细胞激活内引起小胶质细胞激活，并在1-3天达到峰值（过渡和早期维护阶段）。 Take together with further behavioral studies using inhibitors for microglial and astrocytic activation, and MAPK inhibitors, it is suggested that early microglia activation contributes to the initial induction of chronic pain and precipitates, in turn, the subsequent and sustained astrocytic activation, which is implemented in the transition and maintenance of the persistent pain state.In the inflammatory (carrageenan/kaolin) and神经性疼痛（部分坐骨神经结扎（PSNL））…更多的大鼠模型，主要在星形胶质细胞中表达的神经胶质谷氨酸转运蛋白GLT-1的总表达或膜定位，改善了脊髓中的星形胶质细胞。通过重组腺病毒将GLT-1转移到脊髓中，降低了炎症机械性痛觉过敏和PSNL诱导的异常性疼痛（神经性疼痛）的诱导，尽管它对急性机械和热疼痛没有影响。 These results suggest that dysfunction of GLT-1 by decreasing expression of intracellular trafficking in astrocytes contributes to the induction of chronic pain.Finally, to elucidate the molecular mechanisms underlying GLT-1 trafficking in astrocytes, we constructed a recombinant adenovirus expressing EGFP-tagged GLT-1 and analyzed time-lapse imaging of GLT-1 dynamics in live星形胶质细胞。在大鼠星形胶质细胞 - 神经元混合培养物中，用谷氨酸治疗迅速诱导的簇的形成和GLT-1通过内吞途径的细胞内运输。此外，我们的结果表明，Na^+的影响通过GLT-1与底物传输相关，但不能刺激谷氨酸受体和细胞内Ca^<2+>信号传导，从而触发GLT-1簇。较少的

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慢性疼痛治療標的としてのグリア細胞に関する研究

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• 发表时间: 2007
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