MICA: A comprehensive genomic and functional approach to discover new ion channel targets for human pain treatment

疼痛很常见，每6个成年人中就有1人受到影响。疼痛通常也很复杂；由割伤、烧伤或骨折引起的突然疼痛（痛觉性疼痛），或与癌症或慢性损伤相关的长期疼痛（神经性疼痛），或更常见的是两种类型的混合。目前还不可能知道一个人遭受了多少痛苦，也不可能准确地比较人与人之间的痛苦。此外，很难确定疼痛的起源，我们知道，一旦疼痛开始，它可能会自我延续，这可能是由于脊髓或大脑的继发性变化。我们也都经历过严重或持续时间长的疼痛所导致的抑郁和衰弱。最后，对于轻度疼痛和短暂的痛觉性疼痛，疼痛治疗通常是成功的；然而，对慢性疼痛的治疗效果要差得多，而且往往会导致副作用。我们和其他人之前已经证明，一类被称为离子通道的基因中的某些成员对产生疼痛至关重要。离子通道基因为位于神经元表面的蛋白质编码，这些蛋白质要么检测到疼痛并将其转化为电压信号，要么对其他检测到疼痛并放大其信号的蛋白质做出反应。我们发现一种叫做SCN9A的离子通道基因可以控制所有的痛觉性疼痛（在没有SCN9A基因的人身上导致一种叫做先天性疼痛不敏感的情况），另一种离子通道基因HCN2控制神经性疼痛（这次在小鼠研究中，没有HCN2基因的小鼠没有感觉到任何神经性疼痛）。在没有SCN9A的人和没有HCN2的小鼠中，缺乏痛觉是唯一的特征。这是非常重要的，并表明如果你能设计一种药物来阻断SCN9A和/或HCN2，你将有一种新型的无副作用的镇痛药。我们现在想寻找更多的离子通道，它们是使人们感到疼痛的机制的一部分。我们采用了一种新颖的方法，将三组感到极度疼痛的人分为两组：一组是患有严重神经性疼痛的人，在其他治疗方法失败后，他们被转介到剑桥的一家专门的疼痛诊所。这些人第一次经历疼痛有多种原因，但他们的特征是持续的疼痛变得越来越严重，使他们无法正常工作和运作。这个群体目前非常难以治疗，对我们的社会和NHS来说是一个重大问题。我们的第二组是在第一次分娩时不需要止痛的妇女——只占剑桥罗茜妇产医院妇女的1%。我们不知道这些妇女是坚忍的，只是决定不服用任何药物，分娩很快，还是有很高的疼痛阈值（可能是混合的），但最重要的是，这些妇女中的一些家庭成员在第一次分娩时同样不需要止痛药，这强烈表明这可能是一种遗传特征。我们的第三组是非常罕见的具有极端痛觉的家庭——要么感觉不到疼痛，要么很早就出现严重的使人虚弱的疼痛。正是通过对这个群体的研究，我们发现了SCN9A。我们将从这三个队列中选择300名疼痛最严重的人，并对他们所有的离子通道基因进行测序。我们正在寻找的是离子通道基因的变化，这将改变它们的工作方式。如果我们在病人身上发现了一个离子通道基因的改变，比如患有严重神经性疼痛的病人，然后在实验室里发现这个突变改变了离子通道的工作方式，那么这个离子通道可能对神经性疼痛患者的疼痛控制很重要。我们需要对每一个基因进行进一步的研究，以进一步证明其在疼痛中的作用。我们发现的每个离子通道都有可能产生新的镇痛药，从而更好地控制患者的疼痛。

Pain is common, affecting 1 in 6 adults. Pain is also often complex; the sudden pain of a cut, burn or fractured bone (nociceptive pain), or the longer term aching pain associated with cancer or chronic injuries (neuropathic pain) or, more commonly, a mixture of both types. It is currently impossible to tell how much pain a person is suffering or to compare this pain accurately between people. Furthermore it can be difficult to determine the origin of pain, and we know that once pain has started it can become self-perpetuating probably due to secondary changes in the spinal cord or brain. We also all have experienced the depression and debilitation pain can cause if it is either severe or long lasting. Finally, pain treatment if often successful for mild pain and short lived nociceptive pain; however treatments for chronic pain are far less effective and often lead to side effects.We, and others, have previously shown that some members of a class of genes called ion channels are essential to produce pain. Ion channel genes code for proteins that sit on the surface of neurons and either detect pain and turn this into a voltage signal, or respond to other proteins that detect pain and amplify their signal. We found that an ion channel gene called SCN9A can control all nociceptive pain felt (causing a condition called Congenital Insensitivity to Pain in people with no working SCN9A gene) and that another ion channel gene HCN2 controls neuropathic pain (this time in mice studies, where the mice with no HCN2 gene did not feel any neuropathic pain). In both people with no SCN9A and mice with no HCN2 the lack of pain sensing was the only feature. This is very important and suggests that if you could design a drug to block SCN9A and/or HCN2 you would have a new type of analgesic without side effects.We now want to look for further ion channels that are part of the mechanism that make people feel pain. We are taking a novel approach by using three groups of people who feel extremes of pain: one group are people with severe neuropathic pain who get referred to a specialized pain clinic in Cambridge after other approaches have failed. These people have multiple reasons why they first experienced pain but are distinguished by their persistent pain becoming more severe and stopping them working and functioning normally. This group is currently extremely difficult to treat and is a significant problem for our society and the NHS. Our second group consists of women who don't need pain relief during their first delivery - constituting only 1% of women in the Rosie Maternity Hospital in Cambridge. We don't know whether these women are stoical, just determined not to have any drugs, have a quick labour, or have a very high pain threshold (probably a mix), but most importantly some of these women have other family members who similarly didn't need analgesia during their first labour strongly suggesting that this may be a genetic trait. Our third group if of very rare families with extremes of pain sensing - either feeling no pain or very early onset of severe debilitating pain. It is from researching this group that we found SCN9A.We will select the 300 people from these three cohorts with the most severe pain findings and sequence all of their ion channel genes. What we are looking for is changes in ion channel genes that will change the way they work. If we find an ion channel gene change in a patient, say with severe neuropathic pain, and then find that in the laboratory that the mutation alters the way the ion channel works, then that ion channel could be important for pain control in humans with neuropathic pain. We will need to perform further studies on each gene we identify to provide further proof of its role in pain. Each ion channel we identify has the potential to generate new analgesics leading to better pain control for our patients.