Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain.
Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain.
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损伤引起的原发性兴奋性变化以及对神经性疼痛的影响。
DOI：
10.7554/elife.02370
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发表时间：
2014-04-01
期刊：
影响因子：
7.7
通讯作者：
Prescott SA
中科院分区：
文献类型：
--
作者：
Ratté S;Zhu Y;Lee KY;Prescott SA
尽管有许多药物靶点，神经性疼痛仍然难以治疗。在这里，我们为这种难处提供了一种新颖的解释。计算机模拟预测，当分子病理达到临界点（临界）时，与神经性疼痛相关的初级传入兴奋性的质的变化是通过尖峰起始动力学的开关产生的，并且这个临界点可以通过几种不同的分子病理（退化）来达到。我们通过药理学阻断天然电导和/或电生理学插入虚拟电导，对这些预测进行了实验测试。多种不同的手法分别成功复制或逆转naïve或神经损伤大鼠的初级传入神经病变，从而证实了预测的临界性及其退化基础。退行性意味着几种不同的分子病理单独足以引起高兴奋性，并且由于几种这样的病理在神经损伤后共同发生，因此没有单一的病理是唯一必要的。因此，单靶点药物可以通过几个离子通道中的任何一个的不适应可塑性来规避。虽然与受伤相关的疼痛是不愉快的，但它通常有一个重要的目的：让你避免它的来源。然而，有些痛苦似乎不知从何而来。令人沮丧的是，这种类型的疼痛，被称为神经性疼痛，对普通止痛药没有反应，因此很难治疗。传递疼痛和其他感觉信息的神经元是通过电信号来实现的。作为对刺激的反应，离子穿过神经元膜上的通道，从而导致膜电位的变化。当这种变化足够大时，就会产生一个电压尖峰：这个信号最终被传输到大脑。当某些神经元太容易或太频繁地放电时，就会产生神经性疼痛。这种过度兴奋会让痛苦的事情变得更糟，或者让本不应该受到伤害的事情变得更痛。为了防止这种情况的发生，人们进行了广泛的研究，以确定针对特定类型离子通道并阻断它们的药物。然而，尽管发现了许多有希望的药物，这些药物在临床试验中却令人沮丧地无效。ratt<s:1>等人通过模拟和实验，研究了一种神经元的行为，这种神经元通常会传递有关触觉的信息，但大脑有时会将这些信息误解为疼痛。在这些模拟中，增加通过细胞膜的离子流量最终会导致一个“临界点”被越过，从而引发尖峰模式的戏剧性、不连续的变化。然而，由于几种不同类型的离子通道对电流有贡献，因此有几种不同的方法可以跨越临界点。这种通过多种方式产生相同结果的能力是复杂系统的共同特征。它被称为简并性，它使系统更加健壮，因为如果实现该结果的特定尝试失败，仍然可以实现给定的结果。ratt<s:1>等人的工作有助于解释为什么仅针对一种离子通道的药物可能无法缓解神经性疼痛：其他几种离子通道中的任何一种的不适应变化都可能规避治疗效果。DOI: http://dx.doi.org/10.7554/eLife.02370.002
Neuropathic pain remains notoriously difficult to treat despite numerous drug targets. Here, we offer a novel explanation for this intractability. Computer simulations predicted that qualitative changes in primary afferent excitability linked to neuropathic pain arise through a switch in spike initiation dynamics when molecular pathologies reach a tipping point (criticality), and that this tipping point can be reached via several different molecular pathologies (degeneracy). We experimentally tested these predictions by pharmacologically blocking native conductances and/or electrophysiologically inserting virtual conductances. Multiple different manipulations successfully reproduced or reversed neuropathic changes in primary afferents from naïve or nerve-injured rats, respectively, thus confirming the predicted criticality and its degenerate basis. Degeneracy means that several different molecular pathologies are individually sufficient to cause hyperexcitability, and because several such pathologies co-occur after nerve injury, that no single pathology is uniquely necessary. Consequently, single-target-drugs can be circumvented by maladaptive plasticity in any one of several ion channels. DOI: http://dx.doi.org/10.7554/eLife.02370.001 Although the pain associated with an injury is unpleasant, it normally serves an important purpose: to make you avoid its source. However, some pain appears to arise from nowhere. Frustratingly, this type of pain, known as neuropathic pain, does not respond to common painkillers and is thus very difficult to treat. The neurons that transmit pain and other sensory information do so using electrical signals. In response to a stimulus, ions travel through channels in the membrane of a neuron, which leads to a change in the electrical potential of the membrane. When this change is large enough, a voltage spike is produced: this signal is ultimately transmitted to the brain. When certain neurons fire too easily or too often, neuropathic pain can arise. This hyperexcitability can make something painful feel even worse, or it can make things hurt that shouldn’t. To prevent this, extensive research has been devoted to identify drugs that target particular types of ion channels and block them. However, despite the discovery of many promising drugs, those drugs have been frustratingly ineffective in clinical trials. Using simulations and experiments, Ratté et al. have examined the behavior of a type of neuron that normally conducts information about touch, but the brain sometimes misinterprets this information as pain. Increasing the flow of ions through the cell membrane in these simulations eventually causes a ‘tipping point’ to be crossed, which triggers a dramatic, discontinuous change in spiking pattern. However, as several different types of ion channels contribute to the current, there are several different ways in which the tipping point can be crossed. This ability to produce the same result by multiple means is a common feature of complex systems. Known as degeneracy, it makes systems more robust, as a given result can still be achieved if one particular attempt to achieve this result fails. The work of Ratté et al. helps to explain why drugs that target just one type of ion channel may fail to relieve neuropathic pain: maladaptive changes in any one of several other ion channels may circumvent the therapeutic effect. DOI: http://dx.doi.org/10.7554/eLife.02370.002