通过计算建模研究 Nav1.8 钠通道的变化对神经性疼痛的影响

IF 2.1 4区 医学 Q2 MATHEMATICAL & COMPUTATIONAL BIOLOGY Frontiers in Computational Neuroscience Pub Date : 2024-05-09 DOI:10.3389/fncom.2024.1327986
Peter Kan, Yong Fang Zhu, Junling Ma, Gurmit Singh
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引用次数: 0

摘要

目的 Nav1.8 的表达仅限于感觉神经元;据推测,该通道在损伤部位的异常表达和功能会导致病理性疼痛。然而,Nav1.8 对神经病理性疼痛的具体贡献并不像它在炎症性疼痛中的作用那样明确。为了研究钠通道 Nav1.8 动力学变化的影响,我们使用 NEURON v8.2 模拟软件构建了基于霍奇金-赫胥黎型电导的尖峰神经元模型。我们构建了一个包含 Nav1.8 通道的神经元体单室模型,其离子机制改编自现有的一些小型 DRG 神经元模型。结果我们发现,Nav1.8 是产生和维持神经元异常电生和过度兴奋的一个重要参数。典型的兴奋性增高主要是由于该通道激活稳态的左移,并进一步受到该通道最大电导和失活稳态的调节。因此,在我们的神经病理性动物模型中,动作电位形状的改变、阈值的降低和感觉神经元重复性发射的增加可能是由 Nav1.8 的这些调节作用协调的。在这项研究中,我们强调了小 DRG 神经元内 Nav1.8 通道功能的变化可能会导致神经病理性疼痛。
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Computational modeling to study the impact of changes in Nav1.8 sodium channel on neuropathic pain
ObjectiveNav1.8 expression is restricted to sensory neurons; it was hypothesized that aberrant expression and function of this channel at the site of injury contributed to pathological pain. However, the specific contributions of Nav1.8 to neuropathic pain are not as clear as its role in inflammatory pain. The aim of this study is to understand how Nav1.8 present in peripheral sensory neurons regulate neuronal excitability and induce various electrophysiological features on neuropathic pain.MethodsTo study the effect of changes in sodium channel Nav1.8 kinetics, Hodgkin–Huxley type conductance-based models of spiking neurons were constructed using the NEURON v8.2 simulation software. We constructed a single-compartment model of neuronal soma that contained Nav1.8 channels with the ionic mechanisms adapted from some existing small DRG neuron models. We then validated and compared the model with our experimental data from in vivo recordings on soma of small dorsal root ganglion (DRG) sensory neurons in animal models of neuropathic pain (NEP).ResultsWe show that Nav1.8 is an important parameter for the generation and maintenance of abnormal neuronal electrogenesis and hyperexcitability. The typical increased excitability seen is dominated by a left shift in the steady state of activation of this channel and is further modulated by this channel’s maximum conductance and steady state of inactivation. Therefore, modified action potential shape, decreased threshold, and increased repetitive firing of sensory neurons in our neuropathic animal models may be orchestrated by these modulations on Nav1.8.ConclusionComputational modeling is a novel strategy to understand the generation of chronic pain. In this study, we highlight that changes to the channel functions of Nav1.8 within the small DRG neuron may contribute to neuropathic pain.
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来源期刊
Frontiers in Computational Neuroscience
Frontiers in Computational Neuroscience MATHEMATICAL & COMPUTATIONAL BIOLOGY-NEUROSCIENCES
CiteScore
5.30
自引率
3.10%
发文量
166
审稿时长
6-12 weeks
期刊介绍: Frontiers in Computational Neuroscience is a first-tier electronic journal devoted to promoting theoretical modeling of brain function and fostering interdisciplinary interactions between theoretical and experimental neuroscience. Progress in understanding the amazing capabilities of the brain is still limited, and we believe that it will only come with deep theoretical thinking and mutually stimulating cooperation between different disciplines and approaches. We therefore invite original contributions on a wide range of topics that present the fruits of such cooperation, or provide stimuli for future alliances. We aim to provide an interactive forum for cutting-edge theoretical studies of the nervous system, and for promulgating the best theoretical research to the broader neuroscience community. Models of all styles and at all levels are welcome, from biophysically motivated realistic simulations of neurons and synapses to high-level abstract models of inference and decision making. While the journal is primarily focused on theoretically based and driven research, we welcome experimental studies that validate and test theoretical conclusions. Also: comp neuro
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