Tissue type plasminogen activator induced in rat dorsal horn astrocytes contributes to mechanical hypersensitivity following dorsal root injury
Tissue type plasminogen activator induced in rat dorsal horn astrocytes contributes to mechanical hypersensitivity following dorsal root injury
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DOI：
10.1002/glia.20483
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发表时间：
2007-04-15
期刊：
影响因子：
6.2
通讯作者：
Noguchi, Koichi
中科院分区：
文献类型：
--
作者：
Kozai, Toyoko;Yamanaka, Hiroki;Noguchi, Koichi
背根损伤可引起脊髓细胞外环境的改变和突触的重组，损伤的初级传入神经的降解和备用末端的发芽。这些变化会影响行为敏感性，有时会导致神经性疼痛。我们假设，神经损伤后，背角细胞外蛋白水解的改变参与了背角神经可塑性的改变。组织型纤溶酶原激活物（Tissue type plasminogen activator, tPA）是一种众所周知的细胞外丝氨酸蛋白酶，参与细胞外基质的修饰，从而导致海马的长期增强等神经可塑性改变。在本研究中，我们发现L4/5根损伤后激活的星形胶质细胞中tPA的显著诱导以及由此导致的背角蛋白水解酶活性的增加。我们还使用根结扎模型研究了tPA活性与机械超敏反应的关系，该模型已用于研究神经根病疼痛行为。鞘内持续给药tPA抑制剂，tPA- stop，在损伤早期（0-4天）以剂量依赖的方式抑制根结扎引起的机械性异常痛。相比之下，在损伤的慢性期（10天）延迟给药tPA-STOP对疼痛行为没有影响。这些数据表明，星形胶质细胞在神经根性疼痛的病理生理中起着重要的作用，星形胶质细胞衍生的tPA和背角的蛋白水解活性可能是根损伤后疼痛的重要因素之一。(c) 2007 Wiley-Liss, Inc。
Dorsal root injury is known to induce alteration of the extracellular environment in the spinal cord and synaptic reorganization with degradation of injured primary afferent and sprouting of spared terminal. These changes affect behavioral sensitivity and sometimes lead to neuropathic pain. We have hypothesized that changes in extracellular proteolysis in the dorsal horn is involved in neuroplastic changes in the dorsal horn after nerve injury. Tissue type plasminogen activator (tPA) is a well-known extracellular serine protease and is involved in the modification of the extracellular matrix, which leads to neuroplastic changes such as long-term potentiation in the hippocampus. In the present study, we found a marked induction of tPA in activated astrocytes following L4/5 root injury and a resultant increase of proteolytic enzymatic activity in the dorsal horn. We also examined the involvement of tPA activity on mechanical hypersensitivity using a root ligation model which has been used for investigating radiculopathy pain behavior. Intrathecal and continuous administration of tPA inhibitor, tPA-STOP, suppressed root ligation-induced mechanical allodynia in a dose-dependent manner during an early stage of injury (0-4 days). In contrast, the delayed administration of tPA-STOP during the chronic stage of injury (10 days) did not affect pain behavior. These data suggest an important contribution of astrocytes in the dorsal horn to the pathophysiology of radiculopathy pain, and astrocyte-derived tPA and the proteolytic activity in the dorsal horn may be one of the essential factors involved in pain following root injury. (c) 2007 Wiley-Liss, Inc.