Further investigation has shown that no one region in this pain network is solely responsible for making us feel pain; it is their collective activity that makes us wince. Tracey and her colleagues explored this process by studying the connectivity between specific regions of the pain network. In some people, the neurons in the regions studied fired in unison. In other people, they weren’t so tightly linked. The more in sync a person’s pain network was, the more likely he or she was to report that a laser pulse felt painful.

Our sensation of pain also depends on outside sources of information beyond the nociceptors. The Oxford team demonstrated this effect with another experiment. They told a group of volunteers that they were part of a study to test the safety of a laser, which would zap their feet. Each zap would hit one of six spots. Some of the spots had already been approved as safe, the subjects were told; others had been approved only with reservation; yet others had not been approved at all because they were susceptible to harm. Asked 
to pay close attention to how the laser felt, the subjects knew which spot would be zapped next by looking at a monitor as they lay in an fMRI scanner.

In reality, the experiment was entirely safe. Yet the volunteers tended to report that the unapproved spots hurt more than the approved ones. The knowledge they got from the scientists influenced their sensation of pain. The fMRI scans revealed that when the subjects saw they were about to be zapped on an unapproved spot, a region of the pain network called the anterior insula became active. The researchers concluded that the anterior insula was integrating information about the experiment with the sensations from the foot, priming the pain network to feel a little stab.

Experiments like Tracey’s show that pain is much more than a direct response to a stimulus. That makes sense when you think about the biological function of pain. Pain helps us defend ourselves from harm, and deciding what’s harmful and what isn’t can require some careful—if unconscious—deliberation. Pain protects us long after we are hurt. If we suffer a bruise or a broken bone, it can remain painful for days or weeks. That prolonged agony may be unpleasant, but it can aid our survival by forcing us to let wounds heal. And pain protects us by stim­ulating and strengthening neural connections in the brain, forcing us to associate the sensation with the memory of what we did to cause it. As time passes, we store the memory of the pain without vividly reliving it every day.

But for millions of people the memory doesn’t fade and the pain doesn’t go away. To 
A. Vania Apkarian, a neuroscientist at Northwestern University, the connection between the living memory and the never-ending pain suggests a glitch in the brain. Ordinary pain might turn chronic, he hypothesizes, when inflammation caused by conditions like arthritis or nerve damage provokes an abnormal rush of signals from nociceptors. When these aberrant signals reach the pain network in the brain, Apkarian argues, they overwhelm it. The brain doesn’t get a chance to forget the pain. Instead it learns to feel it continuously. Eventually the neural connections become so strong that we no longer need the original stimuli anymore. The network begins to sustain itself, continually relearning its pain. It can also send signals back down into the body, turning previously painless sensations into painful ones.

Apkarian’s theory may soon be confirmed in the most meaningful way possible, with a new treatment for chronic pain. The drugs currently used to treat chronic pain—aspirin and morphine along with other opiates—don’t work very well and are often addictive. To develop better drugs, scientists are trying to move beyond trial and error and to base their research on our growing knowledge of what causes pain.

To that end, Min Zhuo, a neuroscientist at the University of Toronto, has been testing out potential painkillers on mice. But first he had to give the animals chronic pain, by crimping a nerve in one of their legs. In a matter of days, the mice developed many of the symptoms—and even some of the brain alterations—seen in people with chronic pain.

Zhuo and his colleagues then sought out compounds that could interfere with the learning that goes on during chronic pain. They focused on the behavior of neurons in a region of the brain called the anterior cingulate cortex, which shows especially intense activity in scans of people with chronic pain. The cingulate cortex contains an abundant amount of an enzyme called AC1. Zhuo wondered if the neural learning that leads to chronic pain was accelerated when levels of the enzyme were high.

As a test, Zhuo’s team genetically engineered mice so that they could not make enzyme AC1. The animals turned out almost entirely normal. They could even sense regular types of pain. But when Zhuo tied off a leg nerve, the mice didn’t develop chronic pain.

Once Zhuo recognized that AC1 is essential for chronic pain, he started the hunt for a drug that could interfere with it. He grew cells that produced enzyme AC1 in culture and then added hundreds of different compounds, hoping that one would latch on to the enzyme and thus block its action. Eventually he and his team found one that did, naming it NB001. When scientists gave an oral dose of NB001 to rats suffering from chronic pain, the animals were rid of their symptoms in just 45 minutes. By latching onto AC1, it seems, the drug prevented the neuronal activity that makes chronic pain possible.

NB001 shows a lot of promise. With its focus on the pain engine in the cingulate cortex instead of the entire brain and nervous system, it is particularly targeted. And there are no obvious side effects in labora­tory animals; the rats suffered no harm to their memory or their ability to learn. Zhuo hopes to launch clinical trials in humans soon.

There is no guarantee that NB001 will work as intended, since people and rats have major biological differences. Tinkering with the anterior cingulate cortex—one of the human brain’s supreme multitaskers, involved not just with pain but also with the regulation of emotion and decision-making—is a delicate process. Unforeseen side effects could easily emerge. 
 Yet even if this specific drug doesn’t reach the marketplace, NB001 represents a milestone. It shows that scientists fighting pain are, at long last, leaving the guesswork behind. Now we know where chronic pain lives.