Department of Biomedical Engineering, University of Connecticut, 260 Glenbrook Road, Storrs, Connecticut 06269, United States.
Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269, United States.
ACS Chem Neurosci. 2021 Oct 6;12(19):3558-3566. doi: 10.1021/acschemneuro.1c00052. Epub 2021 Aug 22.
Recent reports indicate dominant roles of TRAAK and TREK-1 channels, i.e., mechanosensitive two-pore-domain potassium channels (K2P) at the nodes of Ranvier for action potential repolarization in mammalian peripheral nerves. Functional changes in mammalian peripheral nerve conduction by mechanical stretch studied by recording compound action potentials lack the necessary resolution to detect subtle neuromodulatory effects on conduction velocity. In this study, we developed a novel approach that enables single-fiber recordings from individual mouse sciatic nerve axons while delivering computer-controlled stepped stretch to the sciatic nerve trunk. Axial stretch instantaneously increased the conduction delay in both myelinated A-fibers and unmyelinated C-fibers. Increases in conduction delay linearly correlated with increases in axial stretch ratio for both A- and C-fibers. The slope of the increase in conduction delay versus stretch ratio was steeper in C-fibers than in A-fibers. Moderate axial stretch (14-19% of length) reversibly blocked 37.5% of unmyelinated C-fibers but none of the eight myelinated A-fibers tested. Application of arachidonic acid, an agonist to TRAAK and TREK-1 to sciatic nerve trunk, blocks axonal transmission in both A- and C-fibers with delayed onset and prolonged block. Also, the application of an antagonist ruthenium red showed a tendency of suppressing the stretch-evoked increase in conduction delay. These results could draw focused research on pharmacological and mechanical activation of K2P channels as a novel neuromodulatory strategy to achieve peripheral nerve block.
最近的报告表明，TRAAK 和 TREK-1 通道（即机械敏感的双孔域钾通道（K2P））在哺乳动物周围神经的郎飞氏结处发挥主要作用，用于动作电位复极化。通过记录复合动作电位研究哺乳动物周围神经传导的机械拉伸引起的功能变化缺乏检测对传导速度的微妙神经调制作用的必要分辨率。在这项研究中，我们开发了一种新方法，可在向坐骨神经干施加计算机控制的步进拉伸的同时，从单个小鼠坐骨神经轴突进行单纤维记录。轴向拉伸瞬时增加了有髓 A 纤维和无髓 C 纤维的传导延迟。传导延迟的增加与 A 和 C 纤维的轴向拉伸比线性相关。与 A 纤维相比，C 纤维中传导延迟与拉伸比的增加斜率更陡。适度的轴向拉伸（长度的 14-19%）可逆地阻断了 37.5%的无髓 C 纤维，但未阻断测试的 8 根有髓 A 纤维中的任何一根。向坐骨神经干施加花生四烯酸，一种 TRAAK 和 TREK-1 的激动剂，可延迟起始并延长阻断，从而阻断 A 和 C 纤维中的轴突传导。此外，应用拮抗剂钌红显示出抑制拉伸引起的传导延迟增加的趋势。这些结果可以集中研究 K2P 通道的药理学和机械激活作为一种新的神经调制策略，以实现周围神经阻滞。
