Role of voltage-dependent calcium channels in nociceptive transmission under normal and neuropathic conditions

该项目旨在增加我们对生物体如何运作和行为的理解，同时提供可用于开发新药物产品的基础知识。这里的基本知识涉及到在疾病的动物模型中，参与神经细胞信号传导的特定蛋白质的功能如何受到影响。涉及的蛋白质被称为钙通道，我们所模拟的疾病是由神经损伤引起的疼痛。每个人在生命中的某个时刻都会遭受疼痛，据估计，三分之二的老年人每天都会经历某种形式的疼痛。事实上，腰痛等症状的成本比心脏病、中风和抑郁症还要高。疼痛可以由多种原因引起，包括受伤、分娩、头痛、手术或疾病。当然，疼痛是身体的警告系统，对防止我们长时间接触有害物质至关重要。疼痛可能是短暂的，当原因消失时就会消失，这种类型通常被称为“伤害性”疼痛。然而，长期或“慢性”疼痛可能是由神经本身的损伤引起的，称为“神经性”疼痛。神经性疼痛的真正问题在于，能有效治疗痛觉性疼痛的药物，如阿司匹林等普通药物，甚至吗啡等更强的止痛药，在很大程度上是无效的。事实上，治疗神经性疼痛的主要药物加巴喷丁，只对大约三分之一的病人有效，而且只能减轻大约一半的疼痛。因此，很明显，英国的生活质量将受益于对神经病变期间发生的变化的基础研究，因为最终这些知识可能导致引入急需的新药。为了解决这些问题，我们将使用一种常见的神经病变动物模型，通过捆绑脊髓神经来引入损伤。一旦损伤确定，我们就可以监测神经细胞的反应，这些细胞向大脑传递信息，提醒我们疼痛。一种成功阻断这些信号的药物有可能治疗神经性疼痛。神经细胞通过释放神经递质物质与邻近细胞进行交流。这种释放是由钙离子控制的，钙离子通过一种叫做钙通道的蛋白质进入细胞。在我们的动物模型中，我们使用了一种从狼蛛毒液中分离出来的化学物质，它可以选择性地阻断一类钙通道。研究发现，这种化学物质只在神经受损的大鼠中减少交流，而在未受伤的大鼠中则没有。因此，如果我们给患有神经性疼痛的病人同样的化学物质，他们的症状可能会减轻。当然，把毒蜘蛛毒液中发现的化学物质给人服用可能并不明智。然而，如果有必要，化学家可以对化学物质的结构进行细微的改变，使其更安全（或更具选择性）。例如，最近已经开发出一种类似的化学物质，它可以阻断另一种类型的钙通道，并被批准用于治疗神经性疼痛。除了用药物阻断钙通道外，我们还可以通过“敲除”负责产生钙通道的特定基因来从基因上去除钙通道。我们现在可以看到，在缺乏这种特殊钙通道的动物身上，反应是否发生了变化。我们还想找出疼痛信号通路中不同钙通道重要的点，以及这些在我们的动物模型中是如何受到影响的。这些研究将使我们能够选择性地针对特定的通道并避免任何药物副作用。通过结合这些技术，我们不仅可以提供基础研究，还可以为人类医学和医疗保健知识做出贡献，从而提高英国的生活质量。

This project seeks to increase our understanding of how living organisms function and behave and, also, to provide basic knowledge that can be used to develop new products for medicine. The basic knowledge here relates to how the function of specific proteins involved in nerve cell signalling may be affected in an animal model of disease. The proteins involved are called calcium channels and the disease that we model is pain caused by nerve damage. Everybody suffers from pain at some point in their lives, it is estimated that two-thirds of the elderly experience some form of pain on a daily basis. In fact, the costs of symptoms such as lower back pain are greater than heart disease, stroke and depression. Pain can arise from a variety of causes including injury, childbirth, headache, surgery or disease. Of course, pain is the body's warning system, vital to prevent us from prolonged exposure to harmful agents. Pain may be short-lived, disappearing when the cause is withdrawn, this type is usually called 'nociceptive' pain. However, longer-term or 'chronic' pain can arise from damage to nerves themselves, called 'neuropathic' pain. The real problem with neuropathic pain is that medicines that effectively treat nociceptive pain, such as common drugs like aspirin and even stronger painkillers like morphine, are largely ineffective. In fact, the major medicine for neuropathic pain, gabapentin, only works in about one-third of patients, and then only reduces the pain by around half. Therefore, it is clear that the quality of life in the UK would benefit from basic research into changes occurring during neuropathy, as ultimately this knowledge may lead to the introduction of much-need novel medicines. To address these issues, we will use a common animal model of neuropathy, which introduces injury by tying off spinal nerves. Once damage is established, we can monitor responses from the nerve cells that transmit messages to the brain alerting us of pain. A drug that successfully blocks these signals has the potential to treat neuropathic pain. Nerve cells communicate with their neighbours by releasing neurotransmitter substances. This release is controlled by calcium ions, which enter the cell via proteins called calcium channels. Using our animal model, we have applied a chemical isolated from tarantula spider venom which blocks a single class of calcium channels selectively. This chemical was found to reduce communication only in rats suffering from nerve damage, and not in non-injured rats. Therefore, if we were to give the same chemical to patients suffering neuropathic pain, their symptoms may be reduced. Of course, it may not be wise to give people a chemical found in the venom of a poisonous spider. However, chemists can make subtle changes to the structure of the chemical to make it safer (or more selective) if necessary. For instance, a similar chemical, which blocks a different type of calcium channel, has recently been developed and given approval to treat neuropathic pain. In addition to blocking calcium channels with drugs, we can also remove them genetically by 'knocking-out' the specific gene responsible for generating the channel. We can now see if responses are changed in animals that uniquely lack this particular calcium channel. We also want to find out the points in the pain signalling pathway where different calcium channels are important and, also, how these may be affected in our animal model. These studies will allow us to target particular channels selectively and avoid any side-effects of medication. By combining these techniques we will provide not only basic research, but may also contribute to knowledge about human medicine and healthcare that will improve quality of life in the UK.