A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain
A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain
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DOI：
10.1016/j.pain.2010.12.035
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发表时间：
2011-04-01
期刊：
影响因子：
7.4
通讯作者：
Snutch, Terrance P.
中科院分区：
文献类型：
--
作者：
Hildebrand, Michael E.;Smith, Paula L.;Snutch, Terrance P.
电压门控离子通道参与外周伤害性感受器和脊髓的痛觉和传递信号机制。基因敲除和基因敲除实验表明，特定的通道亚型，包括Na(V)1.7和Na(V)1.8钠通道和Ca(V)3.2T型钙通道，起着不同的伤害性感受作用。我们合理地设计和合成了一种新型的小分子有机化合物(Z123212)，它通过选择性地稳定处于缓慢失活状态的通道来调节重组和天然的钠和钙通道电流。电压门控通道的缓慢失活可以在神经元过度兴奋时起到刹车的作用，Z123212被发现以一种状态依赖的方式降低外周伤害性感受器和I/II层脊髓神经元的兴奋性。体内实验证明，口服Z123212对神经病理性疼痛大鼠脊神经结扎模型的热痛敏和触觉超敏有明显的逆转作用，并能在热板法中产生急性抗伤害作用。在治疗相关浓度下，Z123212没有引起明显的运动或心血管不良反应。综上所述，外周和中枢疼痛信号通路中钠和钙通道的状态依赖性抑制可能为一类新型疼痛治疗药物的开发提供了一种协同机制。(C)2011年国际疼痛研究协会。爱思唯尔出版公司版权所有。
Voltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Genetic knockdown and knockout experiments have shown that specific channel isoforms, including Na(V)1.7 and Na(V)1.8 sodium channels and Ca(V)3.2 T-type calcium channels, play distinct pronociceptive roles. We have rationally designed and synthesized a novel small organic compound (Z123212) that modulates both recombinant and native sodium and calcium channel currents by selectively stabilizing channels in their slow-inactivated state. Slow inactivation of voltage-gated channels can function as a brake during periods of neuronal hyperexcitability, and Z123212 was found to reduce the excitability of both peripheral nociceptors and lamina I/II spinal cord neurons in a state-dependent manner. In vivo experiments demonstrate that oral administration of Z123212 is efficacious in reversing thermal hyperalgesia and tactile allodynia in the rat spinal nerve ligation model of neuropathic pain and also produces acute antinociception in the hot-plate test. At therapeutically relevant concentrations, Z123212 did not cause significant motor or cardiovascular adverse effects. Taken together, the state-dependent inhibition of sodium and calcium channels in both the peripheral and central pain signaling pathways may provide a synergistic mechanism toward the development of a novel class of pain therapeutics. (C) 2011 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.