EFFECTS OF A NEW POTENT ANALOG OF TOCAINIDE ON hNav1.7 SODIUM CHANNELS AND IN VIVO NEUROPATHIC PAIN MODELS
EFFECTS OF A NEW POTENT ANALOG OF TOCAINIDE ON hNav1.7 SODIUM CHANNELS AND IN VIVO NEUROPATHIC PAIN MODELS
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DOI：
10.1016/j.neuroscience.2010.05.019
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发表时间：
2010-08-25
期刊：
影响因子：
3.3
通讯作者：
Camerino, D. Conte
中科院分区：
文献类型：
--
作者：
Ghelardini, C.;Desaphy, J. -F.;Camerino, D. Conte
电压门控钠通道在神经性疼痛传递中的作用已得到广泛认可。例如，最近的遗传证据表明，人类 Nav1.7 钠通道亚型在感知痛觉的能力中发挥着至关重要的作用，并且可能是镇痛/抗痛觉过敏药物的重要靶点。在这项研究中，使用膜片钳技术在重组 hNav.1.4 和 hNav1.7 通道上对新合成的托卡尼同源物 NeP1 进行了体外测试，并在通过坐骨神经慢性收缩损伤或奥沙利铂治疗获得的两种持续性神经性疼痛大鼠模型中进行了体内测试。 NeP1 以剂量和用途依赖性方式有效阻断 hNav1.4 和 hNav1.7 通道，其效力远强于托卡尼。重要的是，新化合物表现出显着的依赖于使用的效果，这可能是由于与封闭通道相比对灭活通道具有非常高的亲和力。在两种神经性疼痛模型中，NeP1 在恢复体内痛阈降低方面比托卡尼更有效。在奥沙利铂治疗的大鼠中，NeP1 甚至比参考药物曲马多产生更强、更持久的抗痛觉过敏作用。此外，体内和体外研究表明，与托卡尼相比，NeP1 具有更好的毒理学和药代动力学特征。总体而言，这些结果表明 NeP1 是一种新的有前途的先导化合物，可用于进一步开发治疗神经源性慢性疼痛。 (C) 2010 国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
The role of voltage-gated sodium channels in the transmission of neuropathic pain is well recognized. For instance, genetic evidence recently indicate that the human Nav1.7 sodium channel subtype plays a crucial role in the ability to perceive pain sensation and may represent an important target for analgesic/anti-hyperalgesic drugs. In this study a newly synthesized tocainide congener, named NeP1, was tested in vitro on recombinant hNav.1.4 and hNav1.7 channels using patch-clamp technique and, in vivo, in two rat models of persistent neuropathic pain obtained either by chronic constriction injury of the sciatic nerve or by oxaliplatin treatment. NeP1 efficiently blocked hNav1.4 and hNav1.7 channels in a dose- and use-dependent manner, being by far more potent than tocainide. Importantly, the new compound displayed a remarkable use-dependent effect, which likely resulted from a very high affinity for inactivated compared to closed channels. In both models of neuropathic pain, NeP1 was greatly more potent than tocainide in reverting the reduction of pain threshold in vivo. In oxaliplatin-treated rats, NeP1 even produced greater and more durable anti-hyperalgesia than the reference drug tramadol. In addition, in vivo and in vitro studies suggest a better toxicological and pharmacokinetic profile for NeP1 compared to tocainide. Overall, these results indicate NeP1 as a new promising lead compound for further development in the treatment of chronic pain of neuropathic origin. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.