Tissue plasminogen activator in primary afferents induces dorsal horn excitability and pain response after peripheral nerve injury
Tissue plasminogen activator in primary afferents induces dorsal horn excitability and pain response after peripheral nerve injury
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DOI：
10.1046/j.1460-9568.2003.03080.x
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发表时间：
2004-01
影响因子：
3.4
通讯作者：
H. Yamanaka;K. Obata;T. Fukuoka;Yi Dai;Kimiko Kobayashi;A. Tokunaga;K. Noguchi
中科院分区：
文献类型：
--
作者：
H. Yamanaka;K. Obata;T. Fukuoka;Yi Dai;Kimiko Kobayashi;A. Tokunaga;K. Noguchi
已知纤溶酶原激活物和纤溶酶原的细胞外蛋白酶级联调节神经元可塑性和细胞外基质修饰，并且是参与CNS中产生长时程增强的重要因素。本研究旨在探讨周围神经损伤后纤维蛋白溶酶原激活物在初级传入纤维中的表达及其在伤害性感受通路中的作用。我们发现，诱导组织型纤溶酶原激活剂（tPA）和尿激酶型纤溶酶原激活剂（uPA）的mRNA在大鼠背根神经节坐骨神经切断。tPA的免疫反应性增加，在板层I和II的背角，重要的是，在同一地区观察到的tPA介导的蛋白水解活性的增加。由于未观察到uPA和uPA介导的蛋白水解的免疫反应性，我们进一步检查了tPA对背角兴奋性和神经病理性疼痛行为的影响。鞘内注射tPA的特异性抑制剂可降低轴突切断后背角神经元中电刺激诱导的Fos表达，也可防止部分坐骨神经结扎后热痛觉过敏的发生。这些研究结果表明，由于背根神经节中的mRNA表达，背角中的tPA增加，增加了背角的兴奋性，并在周围神经损伤后的疼痛行为中具有重要作用。tPA介导的背角神经元超敏反应可能是神经病理性疼痛的一种新的分子机制。
The extracellular protease cascade of plasminogen activators and plasminogen are known to regulate neuronal plasticity and extracellular matrix modification, and to be important factors involved in producing long‐term potentiation in the CNS. The purpose of this study is to examine the expression of plasminogen activators in primary afferents and its role in nociceptive pathways after peripheral nerve injury. We found the induction of mRNAs for tissue type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) in the rat dorsal root ganglia following sciatic nerve transection. Immunoreactivity for tPA was increased in laminae I and II of the dorsal horn and, importantly, the increase in proteolytic activity mediated by tPA was observed in the same area. As neither immunoreactivity for uPA nor uPA‐mediated proteolysis was observed, we further examined the effects of tPA on dorsal horn excitability and neuropathic pain behaviour. Intrathecal injection of a specific inhibitor of tPA decreased electrical stimulation‐induced Fos expression in dorsal horn neurons following axotomy, and also prevented the development of thermal hyperalgesia following partial sciatic nerve ligation. These findings suggest that the increased tPA in the dorsal horn due to mRNA expression in the dorsal root ganglia increases the dorsal horn excitability and has an important role in pain behaviour after peripheral nerve injury. The tPA‐mediated hypersensitivity in dorsal horn neurons may be a novel molecular mechanism of neuropathic pain.