Somatosensation and Pain

MRC小鼠遗传学网络为解决一系列人类病理学中的疼痛问题提供了一个引人注目的新机会。疼痛在增加。令人惊讶的是，大约一半的人口有持续的疼痛问题，超过300万英国公民每天都有治疗不足的衰弱疼痛，使他们的生活严重问题。关节炎等许多疼痛性疾病都与衰老有关，随着我们寿命的延长，疼痛的人数也在稳步增加，我们都熟悉阿司匹林类药物作为有效的抗炎止痛药，以及非常有效的阿片类药物的效用，这些药物的副作用可能导致死亡-在美国每年有数千人死亡。为什么我们没有新的有效的止痛药以类似的方式，新的抗癌药物，证明是如此有效？有几个原因。首先，一些在动物模型中效果很好的药物在人类中效果不好。尽管所有有效的止痛药都对小鼠有效，但没有办法绝对肯定有效的啮齿动物止痛药（在基因相同的小鼠中进行测试）将对基因不同的人类有效。其次，我们开始意识到，在不同的疼痛状态（例如关节炎或癌症疼痛）中有不同的机制，甚至男性和女性之间也有不同的疼痛机制。因此，通过更多地了解疼痛机制，我们有更好的机会开发有用的镇痛药物。MRC国家小鼠遗传学网络提出的工作解决了这些问题，并通过纳入大量优秀的疼痛组，提供了比更经典的研究计划更大的附加值。我们只计划研究那些已被证明在人类疼痛、偏头痛或头痛中起关键作用的靶点。这可以通过识别负责人类罕见疼痛状况（疼痛的获得或丧失）的基因来完成。我们有近100个家庭有这样的遗传条件。我们将在转基因小鼠中模拟这些疼痛综合征，并确切地了解疼痛的消失是如何发生的，以及它是否为使用药物化学和分子筛选的经典药物开发提供了一个直接的目标。支配身体所有组织的神经（感觉神经元）几乎是所有疼痛条件所必需的，因此我们将专注于这些损伤感知神经元。神经免疫相互作用是疼痛的关键调节因子，因此我们有专门小组专注于这些疼痛机制，但它们仍然通过感觉神经元起作用。如果我们能够识别出负责特定疼痛的特定类型的感觉神经元，我们就已经开发出了一种技术，可以用一种药物关闭这些神经元中的电活动，这种药物可以让神经在不再使用时恢复。例如，如果在人类疼痛状态下改变的关键基因没有明显的生物活性，那么设计一个明显的药物开发计划可能会很困难。在这种情况下，我们可以利用从DNA测序中获得的信息，通过基因治疗来模拟无痛状态--在我们最初的患者中引入导致无痛的突变。这些研究不仅仅关注疼痛。已知感觉神经元调节免疫反应，并且其自身受到微生物组（肠道细菌）的影响。它们在对感染、损伤和可能在各种代谢紊乱中受损的一般稳态功能的反应中起关键作用。因此，将支持我们理解和治疗疼痛的尝试的转基因小鼠也将对MRC国家小鼠遗传学网络的其他研究小组有价值，对许多疾病具有重要的临床意义。

The MRC Mouse Genetics Network provides a dramatic new opportunity to address the problem of pain in a range of human pathologies. Pain is on the increase. Amazingly, about half the population have an ongoing pain issue, and more than 3 million British citizens have daily inadequately-treated debilitating pain that makes their lives deeply problematic. Many painful condition like arthritis are associated with aging, and as we live longer, the number of people in pain is steadily increasing.We are all familiar with aspirin-like drugs as effective anti-inflammatory pain killers, as well as the utility of the very potent opioid drugs that are limited in their use by side effects that can lead to death - many thousands a year in the United States. Why do we have no new effective pain -killers in an analogous way to the plethora of new anti-cancer drugs that are proving so effective? There are several reasons. Firstly, some drugs that work well in animal models don't work well in humans. Despite the fact that all effective pain killers do work in mice, there is no way to be absolutely sure that an effective rodent pain killer (tested in genetically identical mice) will work in genetically distinct humans. Secondly, we are beginning to realise that there are different mechanisms at play in different pain states (for example arthritis or cancer pain), and even different pain mechanism between males and females. Thus by understanding more about pain mechanisms, we have a much better chance of developing useful analgesic drugs. The work proposed by the MRC National Mouse Genetics Network addresses these questions and by incorporating a large number of excellent pain groups, provides substantial added value over more classical research programmes. We are only planning to work on targets that have been demonstrated to play a key role in human pain, migraine or headache. This can be done by identifying genes that are responsible for rare pain conditions in humans (gain or loss of pain). We have close to 100 families with such heritable conditions. We will model these pain syndromes in genetically modified mice and find out exactly how the loss of pain occurs, and whether it provides a straight-forward target for classical drug development using medicinal chemistry and molecular screens. The nerves that innervate all tissues of the body (sensory neurons) are required for almost all pain conditions, so we will be focusing on these damage-sensing neurons. Neuroimmune interactions are key regulators of pain, and so we have specialist groups focussing on these pain mechanisms, that nonetheless act through sensory neurons. If we can identify particular types of sensory neurons responsible for particular pains, we have developed the technology to switch off electrical activity in these sets of neurons with a drug that allows the nerves to recover when it is no longer administered. It may be difficult if, for example, there is no obvious biological activity associated with the key gene altered in human pain states to devise an obvious drug development program. In this case we can use the information obtained from DNA sequencing to mimic the pain-free state by gene therapy - introducing the very mutations that cause a lack of pain in our original patients. These studies are not solely focused on pain. It is known that sensory neurons regulate the immune response, and are themselves influenced by the microbiome (gut bacteria). They play a key role in responses to infection, injury and a general homeostatic function that may be compromised in various metabolic disorders. Thus the genetically-modified mice that will underpin our attempts to understand and treat pain will also be valuable for other research groups involved in the MRC National Mouse Genetics Network, with significant clinical relevance to many diseases.