Inhibition of protein tyrosine phosphatase 1B in spinal cord dorsal horn of rats attenuated diabetic neuropathic pain.
Inhibition of protein tyrosine phosphatase 1B in spinal cord dorsal horn of rats attenuated diabetic neuropathic pain.
复制标题
抑制大鼠脊髓背角蛋白酪氨酸磷酸酶 1B 可减轻糖尿病神经性疼痛。
DOI：
10.1016/j.ejphar.2018.03.012
复制
发表时间：
2018
影响因子：
5
通讯作者：
Hu Xiao-Dong
中科院分区：
文献类型：
--
作者：
Zhao Ji-Yuan;Yang Li;Bai Hu-Hu;Liu Jiang-Ping;Suo Zhan-Wei;Yang Xian;Hu Xiao-Dong
蛋白酪氨酸磷酸酶1B（Protein tyrosine phosphatase 1B，PTP 1B）可使胰岛素受体去磷酸化，从而导致糖尿病的发生。神经病理性疼痛是糖尿病神经病变引起的严重并发症之一。然而，PTP 1B是否参与糖尿病神经性疼痛的发生在很大程度上尚不清楚。本研究表明PTP 1B定位于Sprague-Dawley大鼠脊髓背角神经元。Western blot分析表明，腹腔注射链脲佐菌素诱导的糖尿病性神经病理性疼痛与蛋白表达增加和脊髓PTP 1B进入兴奋性突触的动态再分布有关。我们发现，PTP 1B操作刺激Src激酶和增强N-甲基-D-天冬氨酸（NMDA）亚型的谷氨酸受体的酪氨酸磷酸化。siRNA介导的PTP 1B基因敲除抑制了注射链脲佐菌素的大鼠的Src活性，降低了NMDA受体磷酸化，减轻了热痛觉过敏和机械异常性疼痛。当通过化学PTP抑制剂或PTP 1B（C215 S）突变体操纵PTP 1B活性时，也实现了对糖尿病神经性疼痛的类似镇痛。这些数据揭示了糖尿病神经病变后大鼠脊髓背角中PTP 1B的调节表达，并证明抑制PTP 1B有利于治疗与糖尿病相关的疼痛超敏反应。
Protein tyrosine phosphatase 1B (PTP1B) has been shown to dephosphorylate and inactivate insulin receptors, which contributes to the pathogenesis of diabetes. Neuropathic pain is one of the severe complications that results from diabetic neuropathy. However, whether PTP1B was involved in the development of diabetic neuropathic pain is largely unknown. The current study illustrated that PTP1B was located in spinal cord dorsal horn neurons of Sprague-Dawley rats. Western blot analysis demonstrated that the diabetic neuropathic pain induced by intraperitoneal injection of streptozotocin was associated with an increased protein expression and a dynamic redistribution of spinal PTP1B into excitatory glutamatergic synapses. We found that PTP1B operated to stimulate Src kinase and enhance the tyrosine phosphorylation of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. The siRNA-mediated knockdown of PTP1B in streptozotocin-injected rats repressed Src activity, decreased NMDA receptor phosphorylation and alleviated the thermal hyperalgesia and mechanical allodynia. A similar analgesia against diabetic neuropathic pain was also achieved when PTP1B activity was manipulated by a chemical PTP Inhibitor or PTP1B(C215S) mutant. These data revealed a regulated expression of PTP1B in spinal cord dorsal horn of rats after diabetic neuropathy, and demonstrated that inhibition of PTP1B was beneficial for the treatment of pain hypersensitivity related to diabetes.