Department of Computational Biology, School of Computer Science and Communication, KTH Royal Institute of Technology, Stockholm, Sweden;
J Neurophysiol. 2014 May;111(9):1721-35. doi: 10.1152/jn.00777.2012. Epub 2013 Dec 26.
Action potential initiation and conduction along peripheral axons is a dynamic process that displays pronounced activity dependence. In patients with neuropathic pain, differences in the modulation of axonal conduction velocity by activity suggest that this property may provide insight into some of the pathomechanisms. To date, direct recordings of axonal membrane potential have been hampered by the small diameter of the fibers. We have therefore adopted an alternative approach to examine the basis of activity-dependent changes in axonal conduction by constructing a comprehensive mathematical model of human cutaneous C-fibers. Our model reproduced axonal spike propagation at a velocity of 0.69 m/s commensurate with recordings from human C-nociceptors. Activity-dependent slowing (ADS) of axonal propagation velocity was adequately simulated by the model. Interestingly, the property most readily associated with ADS was an increase in the concentration of intra-axonal sodium. This affected the driving potential of sodium currents, thereby producing latency changes comparable to those observed for experimental ADS. The model also adequately reproduced post-action potential excitability changes (i.e., recovery cycles) observed in vivo. We performed a series of control experiments replicating blockade of particular ion channels as well as changing temperature and extracellular ion concentrations. In the absence of direct experimental approaches, the model allows specific hypotheses to be formulated regarding the mechanisms underlying activity-dependent changes in C-fiber conduction. Because ADS might functionally act as a negative feedback to limit trains of nociceptor activity, we envisage that identifying its mechanisms may also direct efforts aimed at alleviating neuronal hyperexcitability in pain patients.
动作电位在周围轴突上的起始和传导是一个动态过程，表现出明显的活动依赖性。在患有神经性疼痛的患者中，轴突传导速度的活动调节差异表明，这种特性可能为某些病理机制提供了一些见解。迄今为止，由于纤维的直径较小，直接记录轴突膜电位受到了阻碍。因此，我们采用了一种替代方法，通过构建人类皮肤 C 纤维的综合数学模型来检查轴突传导中与活动相关的变化的基础。我们的模型以与人类 C 伤害感受器记录相匹配的 0.69 m/s 的速度再现了轴突尖峰传播。模型充分模拟了轴突传播速度的活动依赖性减慢（ADS）。有趣的是，与 ADS 最容易相关的特性是轴内钠离子浓度的增加。这影响了钠离子电流的驱动电位，从而产生与实验 ADS 观察到的潜伏期变化相当的变化。该模型还充分再现了体内观察到的动作后兴奋性变化（即恢复周期）。我们进行了一系列控制实验，复制了特定离子通道的阻断以及改变温度和细胞外离子浓度。在没有直接实验方法的情况下，该模型允许针对 C 纤维传导中与活动相关的变化的机制提出具体假设。由于 ADS 可能作为一种负反馈机制起作用，以限制伤害感受器活动的串，我们设想确定其机制也可能指导减轻疼痛患者神经元过度兴奋的努力。
