Alabama to Beijing... and Back: The Search for a Pain Gene

Thursday February 15 2018  xmlns:cs=urn:cs href=#Alabama to Beijing... and Back: The Search for a Pain Gene; Stephen Waxman M.D. Ph.D.

摘要

Pain—“it hurts”—is experienced at some time or another by almost every human being.? When pain is transient, it can protect us, warning us to withdraw from a threatening situation. But pain is not always helpful: if it persists when a noxious stimulus is no longer there, it can invade and change a life. This occurs, for example, in people with neuropathic pain due to traumatic nerve injury, peripheral neuropathies associated with diabetes or chemotherapy, and post-herpetic neuralgia. Chronic pain affects more patients than cancer, heart disease, and diabetes combined.1 And it is often unrelieved or only partially relieved by existing medications, whose side-effects may include double-vision, confusion, sleepiness, or gastrointestinal dysfunction. Some of these drugs can be addictive. There is a clear need for more effective pain medications without these drawbacks. How can we find such medications? Might a clue lie in the human genome? Two patients with diabetes may both suffer from weakness and muscle atrophy due to peripheral neuropathy. In both, the neurologist’s hammer cannot trigger a reflex. But one patient is debilitated by severe neuropathic pain that almost never abates, while the other notices numbness but does not seek medical attention, and goes dancing on the weekend. Might the human genome contain clues about molecules within our bodies that make the difference? Might there be a gene for a master-switch that turns pain on or off? Such questions lead us to the search for families in pain. Rare familial diseases may direct researchers toward therapies effective for common illnesses in “the rest of us.” Consider the statin medications, which control lipid levels within our blood, reducing the risk of heart attack. Crucial to their development was the discovery of rare families with inherited hypercholesterolemia. Mutations in specific genes in these families pointed to the culprit molecules, which became the target of new medications that have effectively lowered the incidence of heart disease in the broad general population. Peripheral Generators of Pain To cure chronic pain, we need to understand where it comes from. Throughout our bodies nerve fibers, issuing from pain-signaling nerve cells in ganglia next to the spinal cord serve as sentries and act as an early-warning system. Pain-signaling dorsal root ganglion (DRG) neurons send peripheral axons to the body surface, gut, bladder, and organs, where they can detect threatening mechanical stimuli such as a pinprick or a blow from a hammer, damaging levels of heat or cold, and irritants such as acid; they send central axons into the spinal cord (Figure 1). Trigeminal ganglion neurons serve the same function for the teeth, eyes, and face. These “first-order” pain-sensing neurons signal the presence of such threats by sending nerve impulses to the spinal cord. Within the spinal cord, these impulses excite “ second-order ” neurons that relay the signal to the brain, where it elicits the experience of pain. It is important to remember that the process of pain signaling begins in the periphery.? Figure 1. ? Dorsal root ganglion (DRG) neurons, with cell bodies within the dorsal root ganglia next to the spinal cord, extend an axon from the body surface and organs, all the way into the spinal cord. Sodium channels within the cell membrane of DRG neurons enable them to produce action potentials (AP). Pain-signaling DRG neurons are excited by injurious levels of pressure, heat, cold, acidity (pH), or irritating chemicals and, in response, send action potentials to the spinal cord which relays them to the brain.? Multiple types of sodium channels, sh

机译：几乎每个人都经历过痛苦或“痛苦”。当疼痛短暂时，它可以保护我们，警告我们退出威胁性局势。但是疼痛并不总是有帮助的：如果在有害刺激不再存在时疼痛持续存在，它就会入侵并改变生活。例如，在因外伤性神经损伤导致神经性疼痛，与糖尿病或化学疗法有关的周围神经病以及疱疹后神经痛的人中会发生这种情况。慢性疼痛影响的患者多于癌症，心脏病和糖尿病的总和。1而且，现有药物通常无法缓解或仅部分缓解这种药物，其副作用可能包括双眼，视线模糊，嗜睡或胃肠道功能障碍。其中一些药物可能会上瘾。显然需要没有这些缺点的更有效的止痛药。我们如何找到这种药物？人类基因组中可能有线索吗？由于周围神经病变，两名糖尿病患者可能同时患有无力和肌肉萎缩。在这两种情况下，神经科医生的锤子都无法触发反射。但是，一名患者因几乎从未减轻的严重神经病性疼痛而虚弱，而另一名患者注意到麻木但未寻求医疗救助，并在周末跳舞。人类基因组是否可能包含与我们体内的分子有关的线索，从而有所作为？可能存在一个可以打开或关闭疼痛的主开关的基因吗？这些问题导致我们寻找痛苦中的家庭。罕见的家族性疾病可能会引导研究人员寻求对“我们其他人”中常见病有效的疗法。考虑他汀类药物，它可以控制我们血液中的脂质水平，减少心脏病发作的风险。对他们的发展至关重要的是发现具有遗传性高胆固醇血症的罕见家庭。这些家族中特定基因的突变指向罪魁祸首分子，分子成为新药的目标，这些药物有效降低了广大人群中心脏病的发病率。周围疼痛的产生者为了治疗慢性疼痛，我们需要了解疼痛的根源。在我们整个身体的神经纤维中，神经节的疼痛信号神经细胞（位于脊髓旁）发出的信号充当哨兵，并作为预警系统。疼痛信号的背根神经节（DRG）神经元将外周轴突发送到体表，肠道，膀胱和器官，在那里它们可以检测到威胁性的机械刺激，例如细刺或锤子击打，破坏高温或低温，和刺激物，例如酸;它们将中枢轴突送入脊髓（图1）。三叉神经节神经元对牙齿，眼睛和面部具有相同的功能。这些“一阶”疼痛感应神经元通过向脊髓发送神经冲动来表示存在这种威胁。这些冲动在脊髓内激发“二阶”神经元，这些神经元将信号传递到大脑，从而引起疼痛。重要的是要记住，疼痛信号传导的过程始于周围。图1。？背根神经节（DRG）神经元在背根神经节内的细胞体紧挨着脊髓，使轴突从体表和器官一直延伸到脊髓。 DRG神经元的细胞膜内的钠通道使它们能够产生动作电位（AP）。疼痛信号的DRG神经元受到压力，热，冷，酸度（pH）或刺激性化学物质的有害水平的刺激，并作为响应将动作电位发送到脊髓，从而将其传递给大脑。多种钠通道，sh

Alabama to Beijing... and Back: The Search for a Pain Gene

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