揭秘无痛生活 是什么缺失导致痛觉失灵呢? [美国媒体]

一种罕见的基因突变,使人生来就感觉不到疼痛。科学家试图研制出一种药物,以期恢复这些人的痛觉。近来,这种药物的研究取得了些微令人惊讶的成功。UCL的研究者们在MRC and Wellcome Trust基金的支持下,发现了导致痛觉失灵的原因。

Revealing the Secret to a Pain Free Life

揭秘无痛生活

People born with a rare genetic mutation are unable to feel pain, but previous attempts to recreate this effect with drugs have had surprisingly little success. Using mice modified to carry the same mutation, UCL researchers funded by the MRC and Wellcome Trust have now discovered the recipe for painlessness.

一种罕见的基因突变,使人生来就感觉不到疼痛。科学家试图研制出一种药物,以期恢复这些人的痛觉。近来,这种药物的研究取得了些微令人惊讶的成功。UCL的研究者们在MRC and Wellcome Trust基金的支持下,发现了导致痛觉失灵的原因。

‘Channels’ that allow messages to pass along nerve cell membranes are vital for electrical signalling in the nervous system. In 2006, it was shown that sodium channel Nav1.7 is particularly important for signalling in pain pathways and people born with non-functioning Nav1.7 do not feel pain. Drugs that block Nav1.7 have since been developed but they had disappointingly weak effects.

“蛋白通道”位于神经细胞的细胞膜,能够让神经信号通过细胞膜,从而保证了神经系统中电信号的传导。在2006年时,科学家发现Nav1.7钠离子通道在痛觉信号传导通路中起到了重要作用,天生Nav1.7通道失效的人感觉不到疼痛。现有的药物可以封闭Nav1.7通道,但是对于恢复痛觉却只有令人失望的极弱效果。

The new study, published in Nature Communications, reveals that mice and people who lack Nav1.7 also produce higher than normal levels of natural opioid peptides.

发表在《Nature Communications》上的一项最新研究揭示了这样一个事实:缺少Nav1.7通道的老鼠和人类体内都产生了超过常人水平的天然阿片类肽。



To examine if opioids were important for painlessness, the researchers gave naloxone, an opioid blocker, to mice lacking Nav1.7 and found that they became able to feel pain. They then gave naloxone to a 39-year-old woman with the rare mutation and she felt pain for the first time in her life. Credit: David Bishop/UCL.

为了验证阿片类物质是否在痛觉失灵中扮演了重要角色,研究员给予缺少Nav1.7的小鼠阿片类拮抗剂纳洛酮,给药后发现这些小鼠变得能够感觉到疼痛了。然后他们将纳洛酮给予一位携带该种基因突变的39岁女士,使得这位女士感受到了人生中的第一次疼痛。来源:David Bishop/UCL

To examine if opioids were important for painlessness, the researchers gave naloxone, an opioid blocker, to mice lacking Nav1.7 and found that they became able to feel pain. They then gave naloxone to a 39-year-old woman with the rare mutation and she felt pain for the first time in her life.

为了验证阿片类物质是否在痛觉失灵中扮演了重要角色,研究员给予缺少Nav1.7的小鼠阿片类拮抗剂纳洛酮,给药后发现这些小鼠变得能够感觉到疼痛了。然后他们将纳洛酮给予一位携带该种基因突变的39岁女士,使得这位女士感受到了人生中的第一次疼痛。

“After a decade of rather disappointing drug trials, we now have confirmation that Nav1.7 really is a key element in human pain,” says senior author Professor John Wood (UCL Medicine). “The secret ingredient turned out to be good old-fashioned opioid peptides, and we have now filed a patent for combining low dose opioids with Nav1.7 blockers. This should replicate the painlessness experienced by people with rare mutations, and we have already successfully tested this approach in unmodified mice.”

“经过十年不尽如人意的药物试验,我们现在终于确定了Nav1.7就是人类痛觉的关键因素,”该篇论文的通讯作者(译者注:原文为senior author,意为该篇论文出自该作者负责的实验室,该作者即为实验室“老板”,但由于国内暂无此专有名词,故取与其近似含义的“通讯作者”作为译名)John Wood 教授(UCL Medicine)说,“而秘密成分竟然是老牌的阿片类肽,我们已经为混合低剂量的阿片类和Nav1.7钠通道阻断剂申请了专利。我们已经在小鼠身上测试成功,只要使用该专利药品,就能重现稀有基因突变者的痛觉失灵感受。”

Broad-spectrum sodium channel blockers are used as local anaesthetics, but they are not suitable for long-term pain management as they cause complete numbness and can have serious side-effects over time. By contrast, people born without working Nav1.7 still feel non-painful touch normally and the only known side-effect is the inability to smell.

广谱钠通道阻断剂被用于局麻,但却不适用于长效疼痛控制,因为阻断剂会造成完全的痛觉失灵,长期使用还有严重的副作用。与之相反,天生Nav1.7失灵的人却可以感受到普通的、不致痛的触觉,而且唯一已知的副作用只有味觉失灵。

Opioid painkillers such as morphine are highly effective at reducing pain, but long-term use can lead to dependence and tolerance. As the body becomes used to the drug it becomes less effective so higher doses are needed for the same effect, side effects become more severe, and eventually it stops working altogether.

阿片类止疼药,例如吗啡,对减轻疼痛有奇效,但是长期使用会导致药物依赖和耐药。当身体渐渐习惯了该种止疼药后,就需要提高剂量才能保证药效不变,但是副作用也会随之加重。最终,身体会完全对这种止疼药无感。

“Used in combination with Nav1.7 blockers, the dose of opioid needed to prevent pain is very low,” explains Professor Wood. “People with non-functioning Nav1.7 produce low levels of opioids throughout their lives without developing tolerance or experiencing unpleasant side-effects. We hope to see our approach tested in human trials by 2017 and we can then start looking into drug combinations to help the millions of chronic pain patients around the world.”

“在与Nav1.7钠离子通道阻断剂共同使用时,仅需要极低剂量的阿片类药物就能够止疼,”Wood教授解释道,“天生Nav1.7失灵的人会在肝脏中产生低水平的阿片类物质,且不会出现耐药或者令人不适的副作用。我们希望在2017年前开始人体药物试验,然后我们就可以开始考察这种二联用药,以帮助全世界上百万饱受慢性疼痛折磨的患者。”

The findings were made possible by the use of ‘transgenic’ mice, meaning they were modified to carry genetic material from another organism – in this case, the mutation that prevents humans from feeling pain. Precise physiological experiments showed that the nervous systems of the transgenic mice contained around twice the levels of naturally-produced opioids as unmodified mice from the same litter.

之所以能取得如此科研成果,很大一部分原因是“转基因”小鼠的使用。所谓“转基因”小鼠,就是指这些小鼠被改造为携带其他生物的遗传物质——在这个研究中,携带的就是阻止了人类疼痛感的突变基因。精密的生理学实验显示,同一窝小鼠中,转基因小鼠神经系统内含有的自身产生的阿片类物质的水平是普通小鼠的2倍。

“Our results reaffirm the clinical relevance of transgenic mouse models for human diseases,” says Professor Wood. “Studying the mice showed us what was going on in the nervous system that led to painlessness and our findings were directly translatable to humans, as confirmed by the painless patient. Without the work in transgenic mice, none of this would have been possible and we still wouldn’t know how to replicate the effects to help people suffering from chronic pain.”

“我们的研究成果重申了建立转基因老鼠模型与人类疾病临床研究之间的联系,”Wood教授说,“研究转基因小鼠能够告诉我们是什么导致了神经系统产生痛觉失灵的症状,并且能够将我们的研究成果直接转用到人类身上,这点已经在我们的无痛患者身上得到证实。如果没有在转基因小鼠身上的研究,我们不可能发现人类痛觉失灵的原因和恢复方法,也不可能知道怎样重现痛觉失灵以帮助那些忍受着慢性疼痛折磨的患者。”

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