Somatosensation and Pain

MRC小鼠遗传学网络为解决一系列人类病理中的疼痛问题提供了一个引人注目的新机会。痛苦在增加。令人惊讶的是，大约有一半的人有持续的疼痛问题，超过300万的英国人每天都有治疗不当的使人衰弱的疼痛，这使他们的生活陷入了严重的问题。许多疼痛的疾病，如关节炎，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消炎止痛药，以及非常有效的阿片类药物的效用，这些药物的使用受到可能导致死亡的副作用的限制-在美国每年有数千人。为什么我们没有新的有效的止痛药，就像大量新的抗癌药物被证明是如此有效一样？有几个原因。首先，一些在动物身上有效的药物在人类身上并不有效。尽管事实上所有有效的止痛药对老鼠都有效，但没有办法绝对确定一种有效的啮齿动物止痛药（在基因相同的老鼠身上测试）对基因不同的人类也有效。其次，我们开始意识到不同的疼痛状态（例如关节炎或癌症疼痛）有不同的机制在起作用，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，并结合了大量优秀的疼痛组，为更经典的研究项目提供了大量的附加价值。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目标。这可以通过识别导致人类罕见疼痛状况（获得或失去疼痛）的基因来实现。我们有近100个家庭有这种遗传性疾病。我们将在转基因小鼠中建立这些疼痛综合征的模型，并确切地找出疼痛的丧失是如何发生的，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）是几乎所有疼痛状况所必需的，所以我们将集中在这些损伤感知神经元上。神经免疫相互作用是疼痛的关键调节器，所以我们有专门的小组专注于这些疼痛机制，尽管如此，它们还是通过感觉神经元起作用。如果我们能识别引起特定疼痛的特定类型的感觉神经元，我们就能开发出一种技术，通过一种药物来关闭这些神经元的电活动，这种药物可以在不再给药时让神经恢复。例如，如果没有明显的生物活性与人类疼痛状态中改变的关键基因相关，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——引入导致原始患者缺乏疼痛的突变。这些研究并不仅仅关注疼痛。众所周知，感觉神经元调节免疫反应，并且本身受微生物组（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体内平衡功能的反应中发挥关键作用。因此，转基因小鼠将支持我们理解和治疗疼痛的尝试，也将对MRC国家小鼠遗传学网络的其他研究小组有价值，与许多疾病具有重要的临床相关性。

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.