Peter Kan, Yong Fang Zhu, Junling Ma, Gurmit Singh
{"title":"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","authors":"Peter Kan, Yong Fang Zhu, Junling Ma, Gurmit Singh","doi":"10.3389/fncom.2024.1327986","DOIUrl":null,"url":null,"abstract":"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 <jats:italic>in vivo</jats:italic> 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.","PeriodicalId":12363,"journal":{"name":"Frontiers in Computational Neuroscience","volume":"68 1","pages":""},"PeriodicalIF":2.1000,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Computational modeling to study the impact of changes in Nav1.8 sodium channel on neuropathic pain\",\"authors\":\"Peter Kan, Yong Fang Zhu, Junling Ma, Gurmit Singh\",\"doi\":\"10.3389/fncom.2024.1327986\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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 <jats:italic>in vivo</jats:italic> 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.\",\"PeriodicalId\":12363,\"journal\":{\"name\":\"Frontiers in Computational Neuroscience\",\"volume\":\"68 1\",\"pages\":\"\"},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2024-05-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Frontiers in Computational Neuroscience\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3389/fncom.2024.1327986\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MATHEMATICAL & COMPUTATIONAL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Computational Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/fncom.2024.1327986","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MATHEMATICAL & COMPUTATIONAL BIOLOGY","Score":null,"Total":0}
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.
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