Spinal astrocytic activation contributes to mechanical allodynia in a mouse model of type 2 diabetes
Spinal astrocytic activation contributes to mechanical allodynia in a mouse model of type 2 diabetes
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DOI：
10.1016/j.brainres.2010.10.044
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发表时间：
2011-01-12
期刊：
影响因子：
2.9
通讯作者：
Dou, Ke-Feng
中科院分区：
文献类型：
--
作者：
Liao, Yong-Hui;Zhang, Gui-He;Dou, Ke-Feng
糖尿病神经病理性疼痛(DNP)是2型糖尿病患者生活质量下降的主要原因，但其分子机制尚不清楚。新的研究表明，脊髓神经胶质细胞参与了一些神经病理性疼痛模型。然而，目前尚不清楚在2型糖尿病条件下脊髓神经胶质细胞是否被激活，以及它们是否参与了糖尿病引起的神经病理性疼痛。在目前的研究中，使用表现出明显机械性异位痛觉的db/db 2型糖尿病小鼠模型，我们发现脊髓星形胶质细胞而不是小胶质细胞显著激活。鞘内注射星形胶质细胞特异性抑制剂Lα-氨基己二酸酯可显著减轻db/db小鼠的机械性痛觉异常，而小胶质细胞特异性抑制剂米诺环素对其无明显影响，提示脊髓星形胶质细胞激活参与了db/db小鼠痛觉过敏的发生。进一步的研究旨在确定db/db小鼠星形胶质细胞致痛过敏症的详细机制。结果显示，脊髓激活的星形胶质细胞显著增加白细胞介素1β的表达，这可能通过诱导脊髓背角神经元N-甲基-D-天冬氨酸受体(NMDAR)的磷酸化来增强疼痛传递。这些结果提示，脊髓激活的星形胶质细胞可能是2型糖尿病机械性痛觉异常的重要组成部分，“星形胶质细胞-IL-1β-NMDAR-神经元”通路可能是星形胶质细胞-坐骨神经痛的详细机制。因此，抑制脊髓背角星形胶质细胞的激活可能是治疗DNP的一种新的治疗策略。(C)2010爱思唯尔B.V.保留所有权利。
Diabetic neuropathic pain (DNP) plays a major role in decreased life quality of type 2 diabetes patients, however, the molecular mechanisms underlying DNP remain unclear. Emerging research implicates the participation of spinal glial cells in some neuropathic pain models. However, it remains unknown whether spinal glial cells are activated under type 2 diabetic conditions and whether they contribute to diabetes-induced neuropathic pain. In the present study, using a db/db type 2 diabetes mouse model that displayed obvious mechanical allodynia, we found that spinal astrocyte but not microglia was dramatically activated. The mechanical allodynia was significantly attenuated by intrathecally administrated L alpha-aminoadipate (astrocytic specific inhibitor) whereas minocycline (microglial specific inhibitor) did not have any effect on mechanical allodynia, which indicated that spinal astrocytic activation contributed to allodynia in db/db mice. Further study aimed to identify the detailed mechanism of astrocyte-incudced allodynia in db/db mice. Results showed that spinal activated astrocytes dramatically increased interleukin (IL)-1 beta expression which may induce N-methyl-D-aspartic acid receptor (NMDAR) phosphorylation in spinal dorsal horn neurons to enhance pain transmission. Together, these results suggest that spinal activated astrocytes may be a crucial component of mechanical allodynia in type 2 diabetes and "Astrocyte-IL-1 beta-NMDAR-Neuron" pathway may be the detailed mechanism of astrocyte-incudced allodynia. Thus, inhibiting astrocytic activation in the spinal dorsal horn may represent a novel therapeutic strategy for treating DNP. (C) 2010 Elsevier B.V. All rights reserved.