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首页> 外文期刊>Cellular Physiology and Biochemistry >Blocking Mammalian Target of Rapamycin (mTOR) Alleviates Neuropathic Pain Induced by Chemotherapeutic Bortezomib
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Blocking Mammalian Target of Rapamycin (mTOR) Alleviates Neuropathic Pain Induced by Chemotherapeutic Bortezomib

机译：阻断雷帕霉素（mTOR）的哺乳动物靶标可减轻化疗药物硼替佐米引起的神经性疼痛

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Background/Aims Bortezomib (BTZ) is largely used as a chemotherapeutic agent for the treatment of cancer. However, one of the significant limiting complications of BTZ is painful peripheral neuropathy during BTZ therapy. Drugs preventing and/or treating the painful symptoms induced by BTZ are lacking since the underlying mechanisms leading to neuropathic pain remain largely unclear. The purposes of this study were to examine 1) the effects of blocking mammalian target of rapamycin (mTOR) on mechanical pain and cold hypersensitivity evoked by BTZ and 2) the underlying mechanisms responsible for the role of mTOR in regulating BTZ-induced neuropathic pain. Methods Behavioral test was performed to determine mechanical pain and cold sensitivity in a rat model. Western blot analysis and ELISA were used to examine expression of mTOR and phosphatidylinositide 3-kinase (p-PI3K) signals, and the levels of substance P and calcitonin gene-related peptide (CGRP). Results Systemic injection of BTZ significantly increased mechanical pain and cold sensitivity as compared with control animals (P< 0.05 vs. control rats). The expression of p-mTOR, mTOR-mediated phosphorylation of p70 ribosomal S6 protein kinase 1 (p-S6K1), 4E–binding protein 4 (p-4E-BP1) as well as p-PI3K was amplified in the dorsal horn of spinal cord of BTZ rats as compared with control rats. Blocking mTOR by intrathecal infusion of rapamycin attenuated mechanical pain and cold hypersensitivity. Blocking PI3K signal also attenuated activities of mTOR, which was accompanied with decreasing neuropathic pain. Inhibition of either mTOR or PI3K blunted enhancement of the spinal substance P and CGRP in BTZ rats. Conclusions The data for the first time revealed specific signaling pathways leading to BTZ-induced peripheral neuropathic pain, including the activation of mTOR and PI3K. Inhibition of these signal pathways alleviates pain. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of peripheral painful neuropathy observed during chemotherapeutic application of BTZ.
机译：背景/目的硼替佐米（BTZ）被广泛用作治疗癌症的化学治疗剂。然而，BTZ的重要局限性并发症之一是BTZ治疗期间的周围神经痛。缺乏预防和/或治疗BTZ引起的疼痛症状的药物，因为导致神经性疼痛的基本机制仍然不清楚。这项研究的目的是检查1）阻断哺乳动物雷帕霉素靶标（mTOR）对BTZ引起的机械性疼痛和寒冷超敏反应的影响，以及2）导致mTOR调节BTZ诱导的神经性疼痛的作用的潜在机制。方法进行行为测试以确定大鼠模型的机械疼痛和感冒敏感性。 Western blot分析和ELISA用于检查mTOR和磷脂酰肌醇3-激酶（p-PI3K）信号的表达，以及P物质和降钙素基因相关肽（CGRP）的水平。结果与对照组动物相比，全身注射BTZ显着增加了机械性疼痛和感冒敏感性（与对照组相比，P＆＃x3c; 0.05）。在脊髓背角中扩增了p-mTOR的表达，mTOR介导的p70核糖体S6蛋白激酶1（p-S6K1），4E结合蛋白4（p-4E-BP1）以及p-PI3K的磷酸化。与对照大鼠相比，BTZ大鼠的脐带。鞘内注入雷帕霉素可阻断mTOR，从而减轻机械疼痛和感冒超敏反应。阻断PI3K信号也减弱了mTOR的活性，这伴随着神经性疼痛的减轻。抑制mTOR或PI3K会削弱BTZ大鼠脊髓物质P和CGRP的增强。结论首次数据揭示了导致BTZ引起的周围神经性疼痛的特定信号通路，包括mTOR和PI3K的激活。抑制这些信号通路可以减轻疼痛。靶向这些信号分子中的一个或多个可能为治疗和管理BTZ化疗期间观察到的周围疼痛性神经病变提供新的机会。

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