Vitaly Napadow, a neuroscientist at Harvard Medical School and Massachusetts General Hospital, studies how the brain perceives pain. To do that, he uses electroencephalography to track the brain wave patterns of patients with chronic lower back pain.
维塔利·拿帕多是美国哈佛医学院和麻省综合医院的神经科学家，他研究的主题是脑部如何觉知疼痛。拿帕多以脑电图追踪慢性腰痛病人的脑波模式进行研究。
More than three decades ago, when Tom Norris was fighting cancer, he underwent radiation therapy on his groin and his left hip. His cancer disappeared and hasn't come back. But Norris was left with a piercing ache that burned from his hip up his spine to his neck.
约三十多年前，汤姆·诺利斯正与癌症苦苦搏斗，鼠蹊部和左臀接受了放射线治疗。他的癌症消失且没有复发，但针刺般的疼痛却自此从他的臀部、脊椎一直延伸到脖子。
Since then, Norris, now 70, has never had a single day free from pain. It cut short his career as an aircraft maintenance officer in the U.S. Air Force. It's been his constant companion, like the cane he uses to walk. On bad days, the pain is so excruciating, he's bedridden. Even on the best days, it severely limits his ability to move about, preventing him from doing the simplest chores, like taking out the garbage. Sometimes the pain is so overpowering, Norris says, that his breathing becomes labored. "It's like I'm drowning."
诺利斯今年已经70岁了，但从那时开始，他没有一天不痛。疼痛使他提前结束美国空军航机保修军官的生涯。那疼痛就像他的拐杖一样，和他形影不离。在痛得厉害的日子，他只能躺在床上。即使在状况最好的时候，也深深限制了他的活动力。诺利斯说，有时候实在痛得太厉害，连呼吸都吃力万分，“我觉得快要淹死了。”
Norris, who lives in a Los Angeles suburb, spoke to me from a long, cushioned bench, which allowed him to go from sitting to lying flat on his back. A tall and genial man, he's become adept at wearing a mask of serenity to hide his pain. I never saw him wince. When his agony is especially intense, his wife of 31 years, Marianne, says she can tell by a certain stillness she sees in his eyes.
诺利斯住在洛杉矶郊区。他和我说话时坐在有垫子的长凳上，这样可以随时躺下让背部放平。他身材高大、待人亲切，已经学会用平静的表情隐藏身体的疼痛。我从没看过他脸部扭曲。
When the pain began to take over his life, Norris sought solace in speaking out. He became an advocate for chronic pain sufferers and started a support group. And for 30 years he has searched for relief. For many of those years he was on fentanyl, a powerful opioid that he says covered his pain "like a thick blanket" but kept him "basically horizontal and zoned out." He has tried acupuncture, which was somewhat helpful, as well as bee stings, magnet therapy, and faith healing, which weren't. Norris now manages his pain with physical therapy, which improves his mobility, and steroids injected into his spine, which quiet his inflamed nerves.
当疼痛开始占满诺利斯的生活，他获得慰藉的方式是勇敢发声。他成为慢性疼痛者的代言人，并成立了支持团体。这30年来，他遍寻缓减疼痛的方法。期间多年他靠的是吩坦尼这种强效的类鸦片药物，他说吩坦尼“就像厚毯子”一般盖住了疼痛，但却让他只能“平平躺着，精神涣散。”他试过针灸，还算有用。也试过蜂螫、磁石疗法、信仰治疗，这些没什么用。诺利斯现在靠物理治疗控制疼痛，这倒是改善了他的行动力，注射到脊椎的类固醇则舒缓发炎的神经。
Like Norris, nearly 50 million people in the United States and millions more around the world live with chronic pain. The causes are diverse, from cancer to diabetes to neurological illnesses and other ailments. But they share a common source of suffering: physical agony that disrupts their lives, intermittently or all the time. It's not uncommon for cancer patients experiencing severe, unrelenting pain after chemotherapy to opt out of treatment in favor of the ultimate salve of dying.
美国有将近5000万人像诺利斯这样与慢性疼痛共存，世界各地还有另外数百万人。引起慢性疼痛的原因各式各样，但痛苦的源头都一样：破坏生活的间歇或持续性肉体疼痛。癌症病患接受了化疗之后，却出现持续又严重的疼痛，使得他们放弃治疗，宁愿选择死亡的终极解脱，这并不是少见的事。
The toll exacted by chronic pain has become increasingly visible in recent years. After doctors in the late 1990s began prescribing opioid medications such as oxycodone to alleviate persistent pain, hundreds of thousands of Americans developed an addiction to these drugs, which sometimes produce feelings of pleasure in addition to easing pain. Even after the risks became evident, the reliance on opioids continued, in part because there were few alternatives. No novel blockbuster painkillers have been developed in the past couple of decades. (Read how science is unlocking the secrets of addiction.)
慢性疼痛造成的代价在近年来益发显著。自从1990年代末、医生开始开立羟考酮之类的类鸦片药物以缓解持续性疼痛之后，有数十万美国人对这类药物依赖成瘾，因为这类药物除了减缓疼痛，有时还能造成愉悦感。即使在这种风险日益明显之后，对类鸦片药物的依赖依旧，原因之一是几乎没有其他替代药物。近几十年来并没有研发出其他新型的明星止痛药。
The misuse of opioid pain relievers—which are ideally suited for short-term management of acute pain—has become rampant across the United States. In 2017, an estimated 1.7 million Americans had a substance abuse disorder stemming from having been prescribed opioids, according to the National Survey on Drug Use and Health. Every day in the U.S., about 130 people die from opioid overdoses—a grim statistic that includes deaths from prescription painkillers as well as narcotics like heroin. (See the toll of the opioid crisis on one Philadelphia street.)
类鸦片止痛药物适合用于急性疼痛的短期治疗，但这类药物的滥用在全美各地都非常严重。根据美国全国药物滥用及健康调查，在2017年，估计约有170万美国人患有因类鸦片药物处方而衍生的物质滥用疾患。美国每天约有130人死于类鸦片药物使用过量。这恐怖的数字包括处方止痛药以及海洛因之类的毒品所造成的死亡。
The quest to understand the biology of pain and find more effective ways to manage chronic pain has taken on fresh urgency. Researchers are making significant strides in detailing how pain signals are communicated from sensory nerves to the brain and how the brain perceives the sensation of pain. Scientists also are uncovering the roles that specific genes play in regulating pain, which is helping to explain why the perception and tolerance of pain vary so widely.
现在我们更迫切地需要了解疼痛的生物学原理，并找出能更有效地控制慢性疼痛的办法。关于感觉神经如何把疼痛信号传递到脑部，还有脑部觉察疼痛感觉的方式，科学家对其中许多细节的了解都已经有了长足进展，他们也正揭露特定基因在疼痛调节中所扮演的角色，有助于解释为什么对疼痛的知觉与耐受性会因人而有这么大的差异。
These advances are radically altering how clinicians and scientists view pain—specifically chronic pain, defined as pain that lasts more than three months. Medical science traditionally regarded pain as a consequence of injury or disease, secondary to its root cause. In many patients, it turns out, pain originating from an injury or ailment persists long after the underlying cause has been resolved. Pain—in such cases—becomes the disease.
这些进展彻底地改变了医生与科学家对疼痛的看法，特别是慢性疼痛，也就是持续三个月以上的疼痛。医学向来认为疼痛是因为受伤或疾病所造成，并不如病因那么重要。但事实是，许多病人源自受伤或疾病的疼痛，却在病因消除之后依然存在许久。在这种例子中，疼痛本身就是疾病。
The hope is that this insight, coupled with the steadily advancing understanding of pain, will lead to new therapies for chronic pain, including nonaddictive alternatives to opioids. Norris and other patients are keen to see those breakthroughs happen. Researchers, meanwhile, are testing promising alternative strategies, such as stimulating the brain with mild electric shocks to alter its pain perception and harnessing the body's intrinsic capacity to soothe its own pain.
这种体认，再加上对于疼痛持续深入的了解，可望为慢性疼痛带来新的疗法，包括类鸦片药物以外的非成瘾性替代药物。诺利斯和其他病人都殷切期盼看到这样的突破。同时，研究人员也在试验潜质可期的其他手段，例如用温和的电流刺激脑部以改变对疼痛的知觉，并善用身体缓和自身疼痛的固有能力。
Clifford Woolf, a neurobiologist at Children's Hospital in Boston who's studied pain for more than four decades, says it's tragic it has taken a "societal catastrophe" for pain to get the attention it deserves from scientists and physicians, but the impetus this has given to pain research is a silver lining. "I think we have the potential in the next few years of really making an enormous impact in our understanding of pain," he says, "and that will definitely contribute to new treatment options."
克利福德.吴尔夫是波士顿儿童医院的神经生物学家，研究疼痛已四十多年。他说在发生了“社会灾难”之后，科学家和医生才对疼痛投注应有的注意，这是悲剧，但因此能刺激对疼动的研究，总算也是困境中的希望。他说：“我认为未来几年内，我们有可能大幅增进对疼痛的了解，这绝对有助于开发新的治疗选项。”
The capacity to feel pain is one of nature’s gifts to humankind and the rest of the animal kingdom. Without it, we wouldn’t reflexively recoil our hand upon touching a hot stove or know to avoid walking barefoot over broken glass. Those actions, motivated by an immediate or remembered experience of pain, help us minimize the risk of bodily injury. We evolved to feel pain because the sensation serves as an alarm system that is key to self-preservation.
能感觉疼痛，是大自然赋予人类及其他动物的礼物之一。如果不能感觉疼痛，我们在摸到热炉子时不会反射性地缩手，也不会知道要避免赤脚踩在碎玻璃上。这些动作是由即时或记忆中的疼痛经验所驱使，能协助我们将身体受伤的风险降到最低。我们演化出痛觉，是因为这种感觉就像是警铃系统，是自我保护的关键。
The sentries in this system are a special class of sensory neurons called nociceptors, which sit close to the spine, with their fibers extending into the skin, the lungs, the gut, and other parts of the body. They’re equipped to sense different kinds of harmful stimuli: a knife’s cut, the heat of molten wax, the burn of acid. When nociceptors detect any of these threats, they send electrical signals to the spinal cord, which transmits them via other neurons to the brain. Higher order neurons in the cortex—the final destination of this ascending pain pathway—translate this input into the perception of pain.
这个警告系统中的哨兵，是一类叫做痛觉受器的特殊感觉神经元，位于靠近脊椎的部位，其神经纤维则延伸到皮肤、肺脏、肠道和身体其他部位，能侦测各种有害的刺激：刀伤、融蜡造成的灼烫、酸性物质造成的灼痛。当痛觉受器侦测到这类威胁后，会发送电子信号到脊髓，由脊髓中其他神经元接力把信息传到脑部。痛觉上传途径的终点是大脑皮质，这里的高阶神经元会把收到的信息转译成痛觉。
Upon registering the pain, the brain attempts to counteract it. Neural networks in the brain send electrical signals down the spinal cord along what’s known as the descending pain pathway, triggering the release of endorphins and other natural opioids. These biochemicals inhibit ascending pain signals, effectively reducing the amount of pain perceived.
大脑察觉到疼痛之后，会尝试加以反制。脑中的神经网络会发出电子信号，从脊髓往下、沿着所谓的下行疼痛路径传送，触发脑内啡和其他天然类鸦片化合物的释放。这些生化成分会抑制上行的疼痛信息，有效降低觉察到的疼痛程度。
Scientists had sketched out this basic schematic of ascending and descending pain pathways when Woolf began working in the field in the 1980s. A soft-spoken man with eyes that seem to brim with kindness, Woolf was struck by the plight of patients he saw in the surgery ward when he was pursuing his medical degree.
吴尔夫在1980年代进入疼痛研究领域时，科学家已经大致描绘出疼痛的上行与下行基本路径。吴尔夫说话轻柔，眼神充满仁慈，念医学院时，他在外科病房中看到受苦的病人后深感震惊。
“It was clear that all were suffering from severe pain,” he says. Woolf felt the senior resident surgeon seemed almost resentful that they were complaining. “I said to the surgeon, ‘Why aren’t you doing anything?’ ” Woolf recalls. “And the surgeon said, ‘Well, what do you expect? They just had an operation. They’ll get better.’ ”
他说：“他们很明显都受到严重疼痛的折磨。”吴尔夫觉得当时的资深住院医生面对病人的抱怨时简直像在生气。他回忆道：“我问他说：『你为何什么都不做呢？』那位医生说：『唉，你想怎样呢？他们才刚动过手术，之后就会好转了。』”
“Pain was a problem the medical profession downplayed—to a substantial extent because there were no safe and effective interventions,” Woolf says. This realization kindled his desire to understand the nature of pain.
吴尔夫说：“医学界过去刻意轻忽疼痛问题，有很大部分是因为没有安全又有效的介入方式。”这项体悟点燃了他对了解疼痛本质的渴望。
Using rats as a model, he set out to learn more about how pain is transmitted. In his experiments, Woolf recorded the activity of neurons in the animals’ spinal cords in response to a brief application of heat to their skin. As he expected, he observed these neurons firing excitedly when signals arrived from the nociceptive neurons. But Woolf made an unexpected finding. After a patch of skin subjected to heat a few times became inflamed, the neurons in the spinal cord attained a heightened state of sensitivity. Merely stroking the area surrounding the previously injured patch caused them to fire.
他透过大鼠实验深入研究痛觉传递的方式。吴尔夫记录下大鼠脊髓中的神经元在皮肤短暂碰触到热之后的反应。他有意料之外的发现。同一块皮肤在重复受到几次热刺激而发炎以后，脊髓中的神经元就进入了更敏感的状态，只是轻轻碰触受伤区域周围，就能让这些神经元活跃起来。
This showed that the injury to the skin had sensitized the central nervous system, causing neurons in the spinal cord to transmit pain signals to the brain even when the input from peripheral nerves was innocuous. Other researchers have since demonstrated this phenomenon—called central sensitization—in humans and shown that it drives various types of pain, such as when the area around a cut or a burn hurts at the slightest touch.
这个发现显示皮肤上的伤口已经让中枢神经系统变敏感，就算周边神经传来的信息是无害的，脊髓中的神经元依然会传送疼痛讯号到脑部。后来其他研究人员证实了人类也有这种名为“中枢神经敏感化”的现象，并且证实这种现象会造成多种疼痛，像是割伤或是烫伤伤口周围，就算只是轻轻碰一下都会痛。
A startling conclusion from Woolf’s work and subsequent research was that pain could be generated in the absence of a triggering injury. This challenged the view held by some doctors that patients who complained of pain that couldn’t be explained by any obvious pathology were likely lying for one reason or another—to get painkillers they didn’t need, perhaps, or to gain sympathy. The pain transmission system can become hypersensitive in the wake of an injury—which is what happened in the rats—but it also can go haywire on its own or stay in a sensitized state well after an injury has healed. This is what happens in patients with neuropathic pain, fibromyalgia, irritable bowel syndrome, and certain other conditions. Their pain is not a symptom; it’s a disease—one caused by a malfunctioning nervous system.
吴尔夫与其他人的后续研究，得出了惊人的结论，也就是即使没有能引发疼痛的损伤，依然可能产生疼痛。这挑战了某些医生的看法，他们认为那些抱怨疼痛、但又没有明确病理解释的病人，可能只是在说谎，不是为了弄到并不需要的止痛药，就是为了搏取同情。疼痛传递系统会在受伤之后变得过度敏感――这就是大鼠身上发生的现象――但也可能莫名的失控，或在损伤复原许久之后依然处于敏感状态。神经病变痛、纤维肌痛、大肠激躁症与其他特定病症的病患就是这样。他们的疼痛并不是症状，而是一种疾病――神经系统失常所造成的疾病。
With advances in growing human stem cells in the lab, Woolf and his colleagues are now creating different types of human neurons, including nociceptors. This breakthrough is allowing them to study neurons in greater detail than was previously possible to determine the circumstances where they become “pathologically excitable,” Woolf says, and fire spontaneously.
在实验室中培养人类干细胞的技术已有进展，吴尔夫和同事现在能培养出各种人类神经元，包括痛觉受器。这项突破让他们能研究前人无法探究的神经元细节，以确定神经元在哪些状况下会变得“病态地敏感”――吴尔夫如此形容――并自发地活跃起来。
Woolf and his colleagues have used lab-grown nociceptors to investigate why chemotherapy drugs cause neuropathic pain. When the nociceptors are exposed to these drugs, they become more easily triggered and begin to degenerate. This likely contributes to the neuropathies that 40 percent of chemotherapy patients endure.
吴尔夫和同事利用实验室培养出来的痛觉受器，研究化疗药物造成神經病变痛的原因。当痛觉受器接触到这些药物后，会变得更容易被触发，而且开始退化。有四成化疗病人会经历的神經病变痛可能就是这个原因造成的。
While scientists like Woolf are advancing the understanding of how pain is transmitted, other scientists have discovered that these signals are just one factor in how the brain perceives pain. Pain, it turns out, is a complex, subjective phenomenon that is shaped by the particular brain that’s experiencing it. How pain signals are ultimately translated into painful sensations can be influenced by a person’s emotional state. The context in which the pain is being perceived also can alter how it feels, as evidenced by the pleasantness of the aches that follow a strenuous workout or the desire for a second helping of a spicy dish despite the punishing sting it delivers to the tongue.
吴尔夫这样的科学家正在推进我们对疼痛传递方式的了解，其他科学家则发现疼痛讯息只是大脑如何感知疼痛的因素之一。事实是，疼痛是一种复杂、主观的现象，由正在经历疼痛之人的脑部所形塑。疼痛信号最后转变成疼痛感觉的过程，也会受个人情绪状态的影响。感知疼痛时所处的情境，也会影响疼痛的感觉，比如激烈健身后产生的酸痛感令人爽快，或尽管一道辛辣美食辣到你舌头都痛了、你却还是想再吃一点。
“You’ve got this incredible capability of altering how those signals are processed when they do arrive,” says Irene Tracey, a neuroscientist at the University of Oxford.
英国牛津大学的神经科学家艾琳.崔西说：“我们有很厉害的能力，能在信息传到的时候改变处理它们的方式。”
A skilled communicator who speaks in rapid-fire sentences, Tracey has spent much of her career trying to bridge the mysterious link between injury and pain. “This is a highly nonlinear relationship, and many things can make it worse or can make it better or could make it very different,” she says.
崔西长于沟通，说话速度很快，研究生涯大半都在尝试了解损伤与疼痛之间的神秘关系。她说：“这两者的关系并不是简单直接的，还有很多因素能够让疼痛加剧或减缓，或非常不同。”
In experiments, Tracey and her colleagues have imaged the brains of human volunteers while subjecting their skin to pinpricks or bursts of heat or smears of cream laced with capsaicin, the chemical compound that makes chili peppers spicy. What the researchers have found has led them to discover a much more complex picture of pain perception than had been previously envisioned. There’s no single pain center in the brain. Instead, multiple regions are activated in response to painful stimuli, including networks that also are involved in emotion, cognition, memory, and decision-making.
崔西和同事在实验中让志愿者在皮肤上接受戳刺、短暂的灼热，或涂上含有辣椒素（让辣椒会辣的化学成分）乳霜的同时进行脑部造影。研究人员从结果发现，疼痛感知的全貌远比先前所想像的更加复杂。大脑中并没有单一的疼痛中心，相反地，在受到疼痛刺激的时候，脑中有多个区域会活跃起来，包括也和情绪、认知、记忆和决策相关的网络。
They also learned that the same stimulus doesn’t produce the same activation pattern every time, indicating that a person’s experience of pain can vary even when the injuries are similar. This flexibility serves us well, raising our pain tolerance in situations that demand it—for instance, when carrying a scorching bowl of soup from the microwave to the kitchen counter. The mind knows that dropping the bowl midway would result in greater misery than the brief anguish caused by holding the bowl, so it tolerates the momentary suffering.
他们也发现，同样的刺激不一定每次都会造成相同的活跃模式，显示就算是类似的创伤，同一个人的疼痛经验也会不一样。这种弹性对我们有好处，可以让我们视情况需要提高对疼痛的耐受度。举例来说，当你把微波炉里滚烫的汤端到厨房流理台上时，头脑知道如果半路汤碗掉了，后果会比拿着碗短暂的疼痛更惨，所以能暂时忍受。
Tracey and her colleagues have shown that fear, anxiety, and sadness can make pain feel worse. In one of their experiments, healthy student volunteers listened to Prokofiev’s deeply melancholic “Russia Under the Mongolian Yoke,” slowed to half speed, and read negative statements such as “My life is a failure.” At the same time, they received a burst of heat on a patch on their left forearm, which had been rubbed with capsaicin. Later the students received the same stimulus as they listened to happier music and read neutral statements such as “Cherries are fruits.” In the sad condition, they reported finding the pain “more unpleasant.”
崔西和同事也证明，恐惧、焦虑和悲伤会使疼痛感觉更严重。在他们的一项实验中，健康的学生志愿者一边聆听以半速播放、普罗高菲夫忧伤的管弦乐曲〈蒙古压迫下的俄国〉，一边阅读像是“我的生活一团糟”之类的负面陈述。同时，实验者对他们左前臂一小片涂了辣椒素的皮肤施热。稍后，这些学生会再度接受同样的刺激，但听的是比较愉快的音乐，并阅读如“樱桃是水果”之类的中性陈述。他们说，在悲伤的情境中，疼痛“更难受。”
Comparing scans of the students’ brains in the two moods, the researchers found that sadness influenced more than just the emotion-regulation circuitry. It led to increased activation in other brain regions, indicating that sadness was physiologically dialing up the pain. “We’ve made people anxious and threatened and fearful,” Tracey says, “and we’ve shown that that makes the actual processing of those signals amplified.”
研究人员比较学生在两种情绪下的脑部扫描结果，发现悲伤所影响的不只是情绪调节回路，也让脑部其他区域比较活跃，显示悲伤会在生理上增强疼痛。崔西说︰“我们让实验对象觉得受到威胁、焦虑恐惧，并证明了这会使得实际处理疼痛信号的过程被放大。”
Strong medication would be needed to dull the pain after surgery for arthritis in her hand, Jo Cameron was informed by her anesthesiologist. But the 66-year-old Scottish woman doubted it. “I bet you any money I will not take any painkillers,” she told him.
裘.卡麦隆的麻醉师告诉她，等她动过手部关节炎手术之后，会需要强效药物缓解疼痛。但这位66岁的苏格兰女士不以为然，她告诉麻醉师：“要赌多少钱都可以，我一点止痛药都不用吃。”
The anesthesiologist looked at her as if she were not fully sane. He knew from experience that the postoperative pain was excruciating. When he came by to check on her after surgery, he was astonished to find that she hadn’t requested so much as the mild analgesic he’d prescribed. “You haven’t even taken paracetamol, have you?” he asked.
麻醉师看她的表情就好像她神智失常似的。根据他的经验，术后疼痛是很难受的。他在手术后回来看她的状况时，却惊讶地发现她连之前开的温和止痛剂都没说要。他问：“你连普拿疼都没吃，对吧！”
“No,” Cameron recalls having replied cheerfully. “I told you I wouldn’t.”
卡麦隆记得自己愉快地回答说：“没吃，我之前就说过了。”
Growing up, Cameron says, she was frequently surprised to discover bruises whose origins were a mystery. When she was nine, she broke her arm in a roller-skating accident, but three days passed before her mother noticed that it was swollen and discolored. Years later, Cameron gave birth to her two children without any pain during delivery.
卡麦隆说，从小到大她经常惊讶地发现身上有不明原因的瘀伤。九岁的时候，她溜滑轮鞋发生意外，手臂骨折，但过了三天，等她母亲注意到她的手臂肿胀变色才发现了这件事。多年后，她生两个小孩时都没有感觉到疼痛。
“I don’t really know what pain is,” she says. “I see people in pain, and I see the grimace, the strain on their faces, and the stress, and I have none of that.”
她说：“我并不真的知道痛是什么感觉。我看到人痛得龇牙咧嘴、表情紧绷，还有那种压力，而我都不会。”
Cameron’s inability to sense physical hurt may be unremarkable to her, but it places her in a rarefied group of individuals who are helping scientists unravel the genetics underlying our ability to feel pain. Her amazed anesthesiologist put her in touch with James Cox, a geneticist at University College London. Cox and his colleagues studied her DNA and found she had two mutations in two neighboring genes, called FAAH and FAAH-OUT. They determined that the mutations reduce the breakdown of a neurotransmitter called anandamide, which helps provide pain relief. Cameron has an excess of the biochemical, insulating her against pain.
卡麦隆无法察觉到身体上的伤害，对她来说或许没有什么，却让她成为极少数的一群人，能帮助科学家解开人类痛觉背后的遗传原因。她的麻醉师惊讶之余，让她连络伦敦大学学院的遗传学家詹姆斯.柯克斯。柯克斯和同事研究了她的DNA，发现她的FAAH和FAAH-OUT这两个相邻的基因上有两个突变。他们判断，这两个突变减缓了神经传递物质极乐酰胺的分解，而这种物质有助缓解疼痛。卡麦隆体内有大量这种生化分子，为她隔绝了疼痛。
Cox has been studying people like Cameron since he was a postdoc at Cambridge in the mid-2000s, when his supervisor, Geoffrey Woods, learned about a 10-year-old street performer in Pakistan who could walk barefoot over hot coals and stick daggers into his arms without so much as a whimper. The boy would earn money from these stunts and then go to the hospital to be treated for his wounds. He was never the subject of a study—he died from head injuries after falling off a roof while playing with friends—but Cox and his colleagues were able to analyze the DNA of six children from the same clan, who showed similar insensitivity to pain. The children each had a mutation in a gene called SCN9A, known to be involved in pain signaling.
2000年代中期，当柯克斯还在剑桥大学做博士后研究时，就已经开始研究像卡麦隆这样的人。当时他的指导教授杰弗里.伍兹听说巴基斯坦有个十岁的街头艺人，可以赤脚走在热炭上、把匕首插进手臂，吭都不会吭一声。小男孩表演这些特技赚钱，然后去医院治疗伤口。他不曾成为研究对象――他跟朋友玩的时候从屋顶上摔下来，头部受伤去世了――但柯克斯和同事在他的亲族中发现有六名儿童也对疼痛无感，并得以分析他们的DNA。这些孩子的SCN9A基因上都有一个突变，而这个基因已知和疼痛信息的传递有关。
The gene makes a protein that is instrumental in the transmission of pain messages from nociceptive neurons to the spinal cord. The protein, christened Nav1.7, sits on the surface of the neuron and serves as a channel for sodium ions to pass into the cell, which enables electrical impulses constituting the pain signal to propagate along the threadlike axon that connects to another neuron in the spinal cord.
这个基因会制造一种蛋白质，在疼痛信息从痛觉神经元传递到脊髓时扮演重要角色。这个蛋白质名为Nav1.7，就位在神经元的表面，担任钠离子进入细胞的信道，让构成疼痛信息的电脉冲可以沿着连接到脊髓中另一个神经元的丝状轴突继续传递下去。
The mutations the researchers discovered in the SCN9A gene yield malformed versions of the Nav1.7 protein that don’t allow sodium ions to pass into nociceptive neurons. With their nociceptors incapable of conducting pain signals, the children were oblivious when they chewed their tongues or scalded themselves. “The beauty of working with these extremely rare families is that you can identify single genes which have the mutation and essentially are human-validated analgesic drug targets,” Cox says.
研究人员在SCN9A基因上发现的突变，会产生畸形的Nav1.7蛋白质，让钠离子无法进入痛觉神经元。由于这些儿童的痛觉受器无法传导疼痛信号，因此他们咬到舌头或烫到自己时都浑然不觉。柯克斯说：“研究这些极端罕见的家族，好处在于能辨识出发生突变的单一基因，基本上就是经过人体验证的止痛药发展目。”
Mutations in the SCN9A gene are also linked to a rare condition called inherited erythromelalgia, or man-on-fire syndrome. Patients who have it face the extreme opposite of insensitivity to pain: a burning sensation on their hands, feet, and face. In warm surroundings, or with slight exertion, the sensation gets unbearably intense, akin to holding one’s hand over a flame.
SCN9A基因上的其他突变也和罕见遗传疾病肢端红痛症有关。这种病又称为“着火人症”，患者对痛觉极度敏感，手脚和脸部会有灼烧感。处于温暖的环境中、或是稍微用力，就会疼痛难当，感觉就像是把手放在火焰上方。
Pamela Costa, a 53-year-old clinical psychologist from Tacoma, Washington, who suffers from the syndrome, describes the pain as “inescapable.” To cope, she has her office temperature set at a chilly 60 degrees. She can sleep only with a complement of four fans around her bed and the air-conditioning on at full blast. In an ironic similarity to individuals with pain insensitivity, the constant burning sometimes makes it hard for Costa to discern hot surfaces, which is how she burned her arm a year ago while ironing.
53岁的帕梅拉.寇斯塔是华盛顿州塔科马的临床心理师，她受这种症状所苦，把那种疼痛形容为“无法摆脱”，因此她的办公室温度必须调到冷凉的摄氏16度，晚上床边要有四个电风扇围着吹，冷气还要开到最强才睡得着。矛盾的是，她和痛觉不敏感的人也有相似之处：持续的灼烧感让她有时候无法注意到热烫的表面，一年前她就是因为这样才会在烫衣服的时候烫伤了手臂。
“I didn’t realize until I heard a hissing sound from my skin getting seared,” she says. “It was the same sensation as I was already having.”
她说：“我听到皮肤烧焦的滋滋声才发现自己烫伤了。那感觉和我本来就有的感觉一样。”
Stephen Waxman, a neurologist at Yale University School of Medicine and one of the world’s foremost experts on nerve conduction, has studied Costa and others like her in his lab at the Veterans Affairs Medical Center in New Haven, Connecticut. Gracious and affable, Waxman speaks animatedly and possesses a cheery disposition despite having made pain his life’s work. He and his colleagues found, as another group had, that man-on-fire patients had mutations in their SCN9A gene. Those mutations have the opposite effect of the one in the pain-free kids from Pakistan, creating Nav1.7 channels that open too easily, allowing sodium ions to flood in even when they shouldn’t.
斯蒂芬.华克斯曼是耶鲁大学医学院的神经学家、也是世界顶尖的神经传导专家，他在康乃狄克州新哈芬退伍军人医学中心的实验室中，研究了寇斯塔和其他像她一样的人。华克斯曼亲切和蔼，虽然以研究疼痛为毕生职志，但他性格开朗，说起话来活力十足。他和同事以及另一个研究团队都发现，着火人症患者的SCN9A基因上有突变，这些突变造成的影响和巴基斯坦那些没有痛觉的孩童完全相反，会让Nav1.7信道太容易开启，甚至在不该让钠离子进入细胞的时候也会打开。
Through lab experiments conducted on neurons in petri dishes, Waxman and his colleagues proved that this was the mechanism by which the SCN9A mutations caused the syndrome in patients like Costa. “We were able to put the channel into pain-signaling neurons and cause them to go BRRRP! when they should be going bop-bop,” says Waxman, referring to the hyperactivity that results from the unabated inflow of sodium ions. In patients with the syndrome, this defect causes nociceptors to bombard the brain with pain messages constantly.
华克斯曼和同事以培养皿中的神经元进行实验，证明了SCN9A上的突变就是经由这个机制引起了像寇斯塔这样的病人所出现的症状。他说：“我们把这个信道置入传递疼痛信息的神经元内，结果这些神经元本来应该是要啪－啪－地慢慢传递信息的，却变成了叭叭叭叭叭这样。”这是因为持续流入的钠离子造成神经元过度活跃。在有这种症状的患者身上，这种缺陷使得痛觉受器持续用疼痛信息轰炸脑部。
The discovery that Nav1.7 can open or close the floodgates to nociceptive pain signals has made the channel an attractive target for researchers looking to develop new pain medications that don’t pose the risk of addiction that opioids do. Opioids work by binding to a protein on the surface of nerve cells called the mu-opioid receptor, causing the receptor to communicate with proteins inside the cell. While the action of some of these proteins alleviates pain, the receptor’s communication with other proteins results in pleasurable feelings. The body develops a tolerance to these drugs, meaning that higher and higher doses are required to trigger the sense of euphoria, which can cause addiction.
发现Nav1.7可以开启与关闭疼痛信号的闸门，让研究人员对这个信道深感兴趣，因为他们希望开发不像类鸦片那样有成瘾风险的治疗疼痛新药。类鸦片化合物会与神经细胞表面上一种名为μ型类鸦片受主的蛋白质结合，让这个受主与细胞内的蛋白质沟通。这种蛋白质中有一些的行为可以减缓疼痛，但受主和其他蛋白质的沟通则会引起愉悦感。身体会对这些药物产生耐受性，也就是说剂量要愈来愈高才能引起欣快感，这就可能造成药物成瘾。
Because Nav1.7 is present only in damage-sensing neurons, a drug that selectively turns off the channel promises to be an effective pain reliever. The sole known side effect is the loss of the sense of smell. Likewise, individuals with the mutation also can’t smell. Existing local anesthetic drugs such as lidocaine indiscriminately block nine sodium channels in the body, including ones that are key to an array of brain functions, which is why doctors must limit their use to numbing patients temporarily. Drug companies are searching for compounds that might be able to block Nav1.7 without disabling other sodium channels, but success has been elusive.
由于Nav1.7只会出现在侦测损伤的神经元上，只阻断这个信道的药物应该可以成为有效的止痛剂。利多卡因等现行的局部麻醉药会无差别地阻断身体中九种钠离子通道，包括对多种脑部功能非常重要的信道，所以医师使用时只限于暂时让病人感觉麻木。
Even so, Waxman is optimistic that the research eventually will lead to better drugs. “I’m confident there will be a new and more effective class of medicines for pain that are not addictive,” he says, his eyes brightening. Then he pauses for a moment and tempers his enthusiasm. “But I can’t begin to attach a time line.”
即使如此，华克斯曼依然乐观，相信相关研究终能催生更好的药物。他说：“我有信心，将来会有一类新的止痛药物，更有效而且不会成瘾。”他说：“但我没办法给一个时间表。”
While the search for new drugs continues, clinicians and researchers are investigating ways to deploy the brain’s intrinsic abilities to modulate pain and lessen the suffering associated with it. And those abilities are impressive. After all, our minds and bodies have been coping with pain for a lot longer than we’ve been studying it.
新药的研究持续进行的同时，医生和研究人员也探索如何运用脑部本身的能力调节疼痛，并且减少疼痛带来的痛苦。这些能力十分惊人。
Take, for example, a recent British study of more than 300 patients with a type of shoulder pain thought to be caused by a bone spur. To relieve the pain, the spur is often removed in surgery. Researchers randomly divided the participants into three groups. One group underwent the surgery. A second group was led to believe it had, but it hadn’t. A third group was asked to return in three months to see a shoulder specialist. The group that had the operation and the one that thought it did reported similar relief from their shoulder pain.
以最近有三百多人参与的一项英国研究为例。参与者都受一种被认为由骨刺造成的肩膀疼痛所苦，为了缓解疼痛，通常是动手术移除骨刺。研究人员把这些病人随机分成三组，一组接受手术，第二组让他们相信自己动了手术、但实际上没有，第三组则是要他们三个月后再回来找肩膀专门医生。实际动手术的那组病人，还有以为自己动了手术的病人，都说自己的肩膀比较不痛了。
“What it showed is that it’s just a placebo. The surgery is not mechanistically doing anything for the pain,” says Oxford’s Irene Tracey, one of the study’s authors. “The pain relief the patients are getting is just driven by a placebo effect.”
牛津大学的艾琳.崔西是这项研究的作者之一，她说：“只是安慰剂效应让病人觉得疼痛缓解了。”
But to Tracey, the outcome isn’t any less important because it shows the placebo effect worked. On the contrary, she says, the study reveals the force of a patient’s belief in the treatment. “What it’s powerfully saying is expectations shape pain,” Tracey says.
但对崔西而言，这个结果并不因为只是展现了安慰剂效果有用而比较不重要。
Other studies have uncovered how a patient’s expectation of reduced pain can translate into actual relief. It seems to activate the brain’s descending pain pathway, leading to the release of opioids synthesized inside the brain that impede the incoming pain signals from the body.
其他的研究也发现，病人对疼痛减少的预期心理能真正转化为疼痛的减少。这种预期可能活化了大脑的下行疼痛路径，引发脑部合成的类鸦片分子释放，阻断了来自身体的疼痛信号。
“This is not just pretend,” Tracey says. “The placebo mechanism hijacks this very powerful system in the brain.”
崔西说：“那不是假装不痛，是安慰剂效应的机制劫持了脑中这个强大的系统。”
Our perception of pain isn’t limited to merely sensing it. The feelings of unpleasantness, fear, and anxiety that accompany the sensation are an integral part of experiencing pain. In a trial at the Cleveland Clinic, researchers led by neurosurgeon Andre Machado used deep brain stimulation (DBS) to target this emotional component of pain in 10 patients who had chronic neuropathic pain after suffering a stroke. The researchers implanted tiny electrodes in a part of the brain involved in processing emotions. Wired to an electronic device inserted in the chest, the electrodes delivered mild shocks to the implantation site at a rate of nearly 200 a second.
人类对于疼痛的知觉并不只限于感受到痛而已，伴随而来的不愉快、恐惧和焦虑等感觉，也是疼痛经验的一部分。克里夫兰医院神经外科医生安德烈.马查多所领导的研究团队，利用深部脑刺激术（DBS），以十位在中风后出现慢性神经病变痛的病人为对象，针对疼痛的情绪因素进行试验。研究人员把细小的电极植入病人脑中处理情绪的部位，另一端连接到安装在胸部的电子装置。电极会对植入部位发出轻微的电击，频率将近每秒200次。
“In several patients, we saw an improvement in their quality of life, in their sensation of well-being, in their independence—without improving the amount of pain,” Machado says.
马查多说：“我们在数名病人身上看到他们的生活质量、身心幸福感与独立行动的能力都改善了――在疼痛未改善的状况下。”
Patients who had scored their pain as a nine on a 10-point scale, for example, continued to give it the same score but reported being able to function better. One of the study subjects, Linda Grubb, describes the treatment as transformative. “It made all the difference in the world as far as being able to go places,” she says, adding that her post-stroke pain had compelled her to spend her days on the couch. “I have so much more energy. My husband says I seem so much happier. It really changed my life completely.”
像是以最高十分为标准、评价自己的疼痛程度为九的病人，虽然持续说自己的痛是九分，但却说自己在生活功能上有进步。其中一位研究对象琳达.葛鲁布说，这种疗法让她的生活有了重大转变：“能出门去别的地方真的改变了一切。”她还补充说中风后的疼痛让她原本整天只能躺在沙发上：“现在我更有活力。我丈夫说我看起来快乐多了。这个疗法彻底改变了我的生活。”
A subsequent part of the study involving both healthy subjects and chronic pain patients gave Machado and his colleagues some insight into why deep brain stimulation appeared to have benefited patients like Grubb. The researchers recorded electrical activity from the brains of participants as they watched a screen while they had two devices strapped to their arms. One device delivered a flash of heat to the skin; the other delivered a harmless buzz. From the visual cue that appeared on the screen, the participants could tell which of the two stimuli they were about to get or if they were going to get nothing at all.
这项研究后续有健康的人和慢性疼痛病人一起参与，让马查多和同事更了解为什么深部脑刺激术能造福葛鲁布这样的病人。研究人员在受试者手臂上绑着两个仪器，让他们一边看屏幕，同时记录下他们脑部的电子活动。其中一个仪器会给皮肤一阵灼烫感，另一个仪器只会发出无害的震动。屏幕上会显示提示图案，让受试者知道接下来会出现哪种刺激，或两种都没有。
The researchers compared the brain activity of participants as they received heat pulses and buzzes or nothing. They found that the brains of chronic pain patients responded similarly when anticipating a painful stimulus and a harmless one, whereas the brains of healthy volunteers showed increased activity in certain regions only when anticipating the heat. When chronic pain patients repeated the experiment while receiving DBS, their brain activity was more similar to that in healthy participants.
研究人员比较了受试者碰到灼烫、震动与没有任何刺激时的脑部活动，发现慢性疼痛患者在预期会造成疼痛的刺激时，反应和预期无害的刺激很类似。而健康志愿者脑中特定区域的活动只有在预期有灼烫时才会增加。若是慢性疼痛患者在接受深部脑刺激术的同时再进行相同实验，他们脑部的活动模式就会比较像健康受试者的。
To Machado and his colleagues, these findings suggest that the brains of chronic pain patients are conditioned by constant exposure to pain to react as if every stimulus is potentially painful, causing the patients to live in distress. The DBS treatment seems to restore a degree of normalcy, enabling the brain “to again distinguish painful from nonpainful, which is what you need in order to be able to function,” Machado says.
马查多和同事认为，这项发现显示，慢性疼痛病人的脑部因为持续暴露在疼痛中而受到制约，把任何刺激都当作潜在的疼痛刺激而加以反应，病人因而活在痛苦之中。深部脑刺激术似乎能让脑部稍微恢复正常，让脑部“能够再度区分疼痛和不疼痛，而这正是让人能正常生活所需要的。”马查多说。
Virtual reality may prove to be another way of reducing pain. I experienced the power of the technique firsthand at the lab of Luana Colloca, a neuroscientist at the University of Maryland. One of Colloca’s assistants strapped a little box onto my left forearm as I sank into a comfortable recliner. The device was similar to the one that Machado’s group had used: Connected to a computer by a cable, it was capable of heating up and cooling down rapidly. In my right hand, I held a controller with a button that I could press to stop the heating on my arm. “Don’t worry; you won’t get burned,” the assistant reassured me.
虚拟实境则可能会是另一种降低疼痛的方式。我在马里兰大学的神经科学家鲁雅娜.可洛卡的实验室中亲身体验了这种技术的力量。我窝在舒适的躺椅上，可洛卡的助理在我左前臂上绑了一个小盒子，这个装置和马查多团队用的仪器相似，上面有电线连到电脑，能快速加热与冷却。我的右手拿著有个按钮的控制器，按下按钮就能够停止手臂上的加热。
In the first few trials, Colloca asked me to press the button as soon as I felt the device getting warm. In the next few rounds, I had to wait a little longer until the device felt uncomfortably hot; in the final series of trials, I had to switch it off only when it felt too hot to bear.
在前几次试验中，可洛卡要我只要一觉得仪器变温了，就马上按钮。接下来几次我必须等久一点，要直到觉得烫得不舒服才按钮。在最后一轮测试中，要觉得烫得受不了才按钮。
Colloca then led me through the same sequence while wearing virtual reality goggles, which immersed me in an oceanic environment. Soothing music played in my ears as I watched dazzlingly colored fish flitting through the water, which was lit up by sunlight filtering down from above. Large iridescent jellyfish floated past. Periodically I felt the device heating up the skin on my forearm, reminding me that I hadn’t gone scuba diving.
之后可洛卡要我戴着虚拟实境眼镜沉浸在海洋世界中，并重复这些试验。我耳中听的是柔和的音乐。散发虹彩的大型水母漂过。每隔一段时间我就感觉到仪器让我前臂的皮肤灼烫。
When the experiment ended, Colloca showed me the temperatures I had allowed the device to reach in all the trials. The readings for what I felt to be “warm,” “hot,” and “unbearably hot” were all higher during the immersive experience. Specifically, the hottest temperature I could handle without flinching had gone up by 2.7 degrees Fahrenheit, to 118 degrees Fahrenheit, which in Colloca’s view was “huge.”
实验结束后，可洛卡让我看每次我忍受仪器加温的数据。在进入沉浸式体验之后，我觉得“温暖”、“灼热”、“烫到受不了”的温度都比之前高了，特别是我能忍受的最高温度提高了摄氏1.5度，来到摄氏47.7度。按照可洛卡的标准，是“差超多。”
“That means you were tolerating a much, much higher level of pain when you were immersed in this environment along with calming music,” she says.
她说：“这表示当你听着平静的音乐、沉浸在虚拟实境中时，能忍受的疼痛程度比之前高很多。”
Scientists don’t yet know for sure why virtual reality has this positive effect on pain tolerance. Some hypothesize it works through distraction: by engaging networks that would otherwise be involved in signaling and perceiving pain. Others speculate that it works by regulating emotions and altering mood. Colloca has shown that the key driver of the benefit is the entertainment provided by the experience, which helps relax patients and reduce their anxiety. Whatever the mechanisms underlying its effectiveness, doctors already are using virtual reality to help patients in acute pain, such as those with severe burns. Colloca believes the strategy also could prove useful in treating chronic pain.
科学家还无法确定为何虚拟实境能促进对于疼痛的耐受程度。有些人认为原因是分心：用到了原本会用于传送和感知疼痛信息的神经网络。也有些人推测是因为调节了情緒、改变了心情。可洛卡的实验显示，这项好处的关键驱力，是这种经验提供的娱乐效果，有助病人放松，并减缓焦虑。不论其效用背后的机制是什么，医生已经开始利用虚拟实境协助有急性疼痛的病人，像是严重烧烫伤的病患。可洛卡相信这个策略用来治疗慢性疼痛应该也会有效。
Every month, Norris leads a meeting of a support group that he helped found a few years ago through the American Chronic Pain Association. The goal is to provide members with informal group therapy, applying the emerging scientific insight that our thoughts and feelings can alter our experience of pain.
诺利斯每个月会主持一次支持团体聚会，这是他数年前透过美国慢性疼痛协会成立的，目的是提供成员非正式的团体治疗，并应用新兴的科学见解，也就是我们的想法和感受能改变疼痛的经验。
I joined Norris at a recent gathering at a Los Angeles church, and he introduced me to the members as they trickled in. (To respect their privacy, I decided not to ask for their last names.) One of them, a slender young man named Brian, shook my hand. When I explained to him, as I did with the others, that I’d come to listen, not to participate, he joked: “Maybe we should punch you in the face so you can relate.”
我参加了诺利斯最近在洛杉矶一间教会举办的聚会，成员陆续抵达时，他介绍我给他们认识。
There were 10 of us in all—five men and five women. We arranged our chairs in a circle and sat down. Resting his cane against a table, Norris settled into his seat and asked the members to share how things had been going for them.
我们一共十个人，五男五女，把椅子排成一圈坐下。
Brian, who suffers from severe abdominal pain that doctors haven’t been able to diagnose, was the first to speak. He described going to a jujitsu class, which he said helped him temporarily forget his pain. “It’s sad that I have to cause myself other pain to forget this one,” he laughed. “I thought of all you guys throughout the week. It made me feel better.”
布莱恩有严重的腹部疼痛，但医生诊断不出原因。他第一个分享，说到正在上柔道课，可以让自己暂时忘却疼痛。他笑道：“要造成另一种疼痛来忘掉原来的疼痛有点悲哀。我整个星期都想到你们大家，让我感觉好多了。”
The members are familiar with each other’s stories. But they seemed bound by an unspoken contract to listen to everyone with full attention, even if they’d heard the same words before. “I called a suicide hot line today,” a woman named Jane said. She suffers from fibromyalgia and complex regional pain syndrome, among other issues. “I’ve complained to my friends so much that I don’t want to call them anymore.”
这些成员熟悉彼此的故事，但他们似乎有默契，会全心聆听每个人说话，即使以前都已经听过。珍有纤维肌痛与复杂性局部疼痛症候群，还有其他问题。她说：“我今天打电话给救命电话。我太常向朋友抱怨了，不想再打电话给他们了。”
Norris told her and the rest of the group that he’s just a phone call away. “Sometimes you just need to scream,” he said. Turning to another woman in the group who’d admitted earlier to being reluctant to reach out for support, he said, “So please, yell.”
诺利斯告诉她和其他成员随时可打电话给他。他说：“有时候你们只是需要大吼一下。”他转向另一位女性。她先前才承认自己不太愿意寻求支持。他说：“所以，拜托大吼吧。”
When the meeting was over, Norris waited for everybody to file out of the room before turning out the lights. I asked what inspired him to organize the monthly meeting. “I find that my experiences are often helpful to others,” he said. But this was just as much about helping himself, he added. “These meetings help me feel like I am still a contributing member of society, and I am not alone in dealing with chronic pain.”
聚会结束后，我问他为什么想举办这个每月聚会，他说：“我发现我的经验对别人通常还满有帮助的。”不过这对他自己也一样有帮助，他补充道：“这些聚会让我觉得自己对社会还能有所贡献，也不是只有自己一个人在面对慢性疼痛。”（全文完）
Yudhijit Bhattacharjee has been a contributing writer since 2017. He is the author of a nonfiction thriller, The Spy Who Couldn’t Spell. David Guttenfelder, Robert Clark, Robin Hammond, and Craig Cutler are frequent contributors. Mark Thiessen is a staff photographer.
尤迪吉特.巴塔查尔吉2017年开始担任特约作者，著有紧张悬疑的纪实作品《不会拼字的间谍》（暂译，原书名为The Spy Who Couldn’t Spell）。大卫.古腾菲尔德、罗伯特.克拉克、罗宾.哈蒙德和克雷格.卡特勒的作品时常出现在杂志中。马克.希森是国家地理专职摄影师。
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