Activation of Dorsal Horn Microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling
Activation of Dorsal Horn Microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling
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DOI：
10.1002/glia.20623
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发表时间：
2008-03-01
期刊：
影响因子：
6.2
通讯作者：
Inoue, Kazuhide
中科院分区：
文献类型：
--
作者：
Tsuda, Makoto;Ueno, Hikaru;Inoue, Kazuhide
疼痛性神经病变是糖尿病最常见的并发症之一，其特征之一是触觉异常性疼痛（对无害刺激的疼痛超敏反应）。然而，触觉异常性疼痛的潜在机制知之甚少。新出现的证据表明，神经损伤后，脊髓中激活的小胶质细胞在触觉异常性疼痛中起着至关重要的作用。然而，它仍然是未知的，是否脊髓小胶质细胞在糖尿病条件下被激活，以及它们是否有助于糖尿病诱导的触觉异常性疼痛。在本研究中，使用链脲佐菌素（STZ）诱导的糖尿病大鼠，显示触觉异常性疼痛，我们发现了几个形态学的变化，激活小胶质细胞在背角。这些变化包括Iba 1和OX-42标记（小胶质细胞的标记物）、肥大形态、突起的厚度和回缩以及活化的小胶质细胞数量的增加。此外，在STZ糖尿病大鼠的背角，细胞外信号调节蛋白激酶（ERK）和上游激酶，Src家族激酶（SFK），这两者都涉及小胶质细胞的功能，被激活的小胶质细胞。此外，通过鞘内给予ERK激活抑制剂U 0126抑制背角中ERK磷酸化，显著缓解糖尿病大鼠现有的长期触觉异常性疼痛。我们还发现，单次给予U 0126降低了异常性疼痛的表达。总之，这些结果表明，激活的背角小胶质细胞可能是糖尿病诱导的触觉异常性疼痛的一个重要组成部分，介导的，部分由ERK信号通路。因此，抑制背角中的小胶质细胞活化可能代表用于治疗糖尿病性触觉异常性疼痛的治疗策略。(c)2008 Wiley-Liss，Inc.
Painful neuropathy is one of the most common complications of diabetes, one hallmark of which is tactile allodynia (pain hypersensitivity to innocuous stimulation). The underlying mechanisms of tactile allodynia are, however, poorly understood. Emerging evidence indicates that, following nerve injury, activated microglia in the spinal cord play a crucial role in tactile allodynia. However, it remains unknown whether spinal microglia are activated under diabetic conditions and whether they contribute to diabetes-induced tactile allodynia. In the present study, using streptozotocin (STZ)-induced diabetic rats that displayed tactile allodynia, we found several morphological changes of activated microglia in the dorsal horn. These included increases in Iba1 and OX-42 labeling (markers of microglia), hypertrophic morphology, the thickness and the retraction of processes, and in the number of activated microglia cells. Furthermore, in the dorsal horn of STZ diabetic rats, extracellular signal-regulated protein kinase (ERK) and an upstream kinase, Src-family kinase (SFK), both of which are implicated in microglial functions, were activated exclusively in microglia. Moreover, inhibition of ERK phosphorylation in the dorsal horn by intrathecal administration of U0126, an inhibitor of ERK activation, produced a striking alleviation of existing, long-term tactile allodynia of diabetic rats. We also found that a single administration of U0126 reduced the expression of allodynia. Together, these results suggest that activated dorsal horn microglia may be a crucial component of diabetes-induced tactile allodynia, mediated, in part, by the ERK signaling pathway. Thus, inhibiting microglia activation in the dorsal horn may represent a therapeutic strategy for treating diabetic tactile allodynia. (c) 2008 Wiley-Liss, Inc.