Identification of molecular pathologies sufficient to cause neuropathic excitability in primary somatosensory afferents using dynamical systems theory.
Identification of molecular pathologies sufficient to cause neuropathic excitability in primary somatosensory afferents using dynamical systems theory.
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DOI：
10.1371/journal.pcbi.1002524
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发表时间：
2012
影响因子：
4.3
通讯作者：
Prescott SA
中科院分区：
文献类型：
--
作者：
Rho YA;Prescott SA
神经损伤引起的疼痛（即神经性疼痛）与疼痛通路上几个点的神经元过度兴奋有关。在初级传入神经中，已经发现了许多损伤引起的变化，但仍不清楚哪些分子变化是必要且足以解释细胞过度兴奋的。为了研究这一点，我们建立了计算模型，重现从去极化开始时以单个尖峰为特征的正常尖峰模式到以整个去极化过程中重复尖峰为特征的神经病理性尖峰模式的转换。足以切换尖峰模式的参数变化也会导致膜电位振荡和爆发，这表明所有三种病理变化在机制上都是相关的。动力学分析证实了这一预测，表明当负责尖峰启动的非线性机制从准分界线交叉切换到亚临界 Hopf 分岔时，兴奋性变化会共同发展。这种转变源于生物物理变化，这些变化使在阈下电位下运行的相反方向的快速激活电导和慢速激活电导之间的竞争产生偏差。单个电导的激活和失活之间的竞争可能会产生类似的偏差，并对兴奋性产生相同的后果。 “偏差”可能是由单独或组合发生的多种分子变化引起的；在后一种情况下，更改可以相互增加或抵消。因此，我们的结果将影响尖峰起始的过程之间的非线性相互作用的病理变化确定为分子水平上简单损伤诱导的变化如何在细胞水平上表现出复杂的兴奋性变化的关键决定因素。我们证明，多种不同的分子变化足以产生兴奋性的神经性变化；然而，鉴于神经损伤引起许多分子变化，这些变化可能单独足以改变尖峰起始，我们的结果表明，不需要单个分子变化来产生神经性兴奋性。对退化因果关系的更深入理解对于我们如何理解和治疗神经性疼痛具有重要意义。神经性疼痛是由神经系统损伤引起的。人们对神经损伤引发的多种分子和细胞变化（并且与神经性疼痛的发展相关）了解很多，但对于这些变化如何引起神经性疼痛却知之甚少。我们的研究重点不是确定神经损伤后发生的变化（这已经成为无数研究的焦点），而是确定哪些变化在功能上很重要。具体来说，我们解释了某些分子变化（单独或组合作用）如何引起初级传入兴奋性的三联神经病理性变化。通过计算建模和非线性动力学分析，我们证明了整个兴奋性变化的三元组是由负责尖峰启动的非线性机制中的单个开关引起的。更进一步，我们证明许多不同的分子变化足以产生这种转换，但如果神经损伤后同时发生不止一种足够的变化，则不需要单个分子变化，这似乎是这种情况。问题在于分子变化是否结合起来达到某个临界点，从而使细胞兴奋性发生质的改变。这凸显了非线性对于神经性疼痛的重要性以及更多计算疼痛研究的需要。
Pain caused by nerve injury (i.e. neuropathic pain) is associated with development of neuronal hyperexcitability at several points along the pain pathway. Within primary afferents, numerous injury-induced changes have been identified but it remains unclear which molecular changes are necessary and sufficient to explain cellular hyperexcitability. To investigate this, we built computational models that reproduce the switch from a normal spiking pattern characterized by a single spike at the onset of depolarization to a neuropathic one characterized by repetitive spiking throughout depolarization. Parameter changes that were sufficient to switch the spiking pattern also enabled membrane potential oscillations and bursting, suggesting that all three pathological changes are mechanistically linked. Dynamical analysis confirmed this prediction by showing that excitability changes co-develop when the nonlinear mechanism responsible for spike initiation switches from a quasi-separatrix-crossing to a subcritical Hopf bifurcation. This switch stems from biophysical changes that bias competition between oppositely directed fast- and slow-activating conductances operating at subthreshold potentials. Competition between activation and inactivation of a single conductance can be similarly biased with equivalent consequences for excitability. “Bias” can arise from a multitude of molecular changes occurring alone or in combination; in the latter case, changes can add or offset one another. Thus, our results identify pathological change in the nonlinear interaction between processes affecting spike initiation as the critical determinant of how simple injury-induced changes at the molecular level manifest complex excitability changes at the cellular level. We demonstrate that multiple distinct molecular changes are sufficient to produce neuropathic changes in excitability; however, given that nerve injury elicits numerous molecular changes that may be individually sufficient to alter spike initiation, our results argue that no single molecular change is necessary to produce neuropathic excitability. This deeper understanding of degenerate causal relationships has important implications for how we understand and treat neuropathic pain. Neuropathic pain results from damage to the nervous system. Much is known about the multitude of molecular and cellular changes that are triggered by nerve injury (and which correlate with development of neuropathic pain), but little is understood about how those changes cause neuropathic pain. Rather than identifying what changes occur after nerve injury (which has already been the focus of countless studies), our study focuses on identifying which changes are functionally important. Specifically, we explain how certain molecular changes, acting alone or in combination, cause a triad of neuropathic changes in primary afferent excitability. Through computational modeling and nonlinear dynamical analysis, we demonstrate that the entire triad of excitability changes arises from a single switch in the nonlinear mechanism responsible for spike initiation. Going further, we demonstrate that many distinct molecular changes are sufficient to produce that switch but that no single molecular change is necessary if more than one sufficient change co-occurs after nerve injury, which appears to be the case. The issue becomes whether molecular changes combine to reach some tipping point whereupon cellular excitability is qualitatively altered. This highlights the importance of nonlinearities for neuropathic pain and the need for more computational pain research.
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影响因子：
14.5
作者：
KOLTZENBURG, M;TOREBJORK, HE;WAHREN, LK
通讯作者：
WAHREN, LK
影响因子：
3.3
作者：
Keller AF;Beggs S;Salter MW;De Koninck Y
通讯作者：
De Koninck Y
影响因子：
13.9
作者：
Costigan M;Scholz J;Woolf CJ
通讯作者：
Woolf CJ
影响因子：
5.3
作者：
Amir, R;Michaelis, M;Devor, M
通讯作者：
Devor, M
DOI：
10.1073/pnas.231499798
发表时间：
2001-11-20
影响因子：
11.1
作者：
Edelman, GM;Gally, JA
通讯作者：
Gally, JA