How Pain Arises–and What Might Stop It

ABEditedAllan Basbaum, PhD, is Professor and Chair of the Department of Anatomy at the University of California, San Francisco, US. Basbaum is a pioneering pain researcher whose lab studies the basic neurobiological mechanisms of pain. He spoke recently by phone with freelance journalist Stephani Sutherland to discuss the basics of pain sensation, how acute pain differs from chronic pain, and how the new understanding of pain could lead to promising new medications. Below is an edited transcript of their conversation.

How does the basic neurobiology of pain sensation work? For example, how do our nerve cells sense pain from the body, like the pain from touching a hot stove?

Nerves conduct electrical impulses, so when a potentially painful stimulus comes along—it could be a painful heat, cold, chemical, or mechanical stimulus—that stimulus will activate the nerve fiber. I say “potentially painful” because pain is a perception, not a stimulus. By “activate,” I mean it will initiate an electrical impulse in that nerve fiber that will then be conducted all the way into the spinal cord where it makes a connection, or a synapse, with other nerve cells in the spinal cord that will then transmit the message to the brain. In most people, this will generate an experience of pain. But if you take certain drugs, for example, they might block pain. So even though a nerve fiber from the skin might transmit an impulse, whether or not it generates pain will depend on a whole variety of things.

Let’s consider a painful heat stimulus. The temperature at which most people will say that something hot is starting to hurt—if you put your foot into a hot bath, for instance—is around 42 to 45 degrees Centigrade. It turns out that there are proteins, called ion channels, in some nerve fibers that are sensitive to heat stimuli—the most famous of these is called TRPV1 (for transient receptor potential vanilloid type 1), a member of a large family of sensory proteins. What’s so interesting about TRPV1 is that not only does it respond to painful heat, but also to capsaicin, which is the active ingredient in hot peppers. Many nerve fibers have the capacity to respond to a variety of plant-derived substances. For example, other channels in nerve fibers respond to cold, and those happen to respond to menthol; there are others that respond to wasabi.

The nerves that sense potentially painful stimuli in the body are distinct from other nerves that sense non-painful touch. Why is that important, and how has that realization guided pain research?

Scientists used to think that there was a rather homogenous population of nerves that innervate the different organs of the body: the skin, muscles, and joints. And they thought that when a stimulus became very intense, that it engaged a population of nerves that were called pain fibers. We now know that there are many distinct classes of nerves. There is a subset of nerve fibers that respond to potentially painful stimuli, but there is also a subset of nerve fibers that don’t respond to painful stimuli.

Within the nerves that respond to painful stimuli, there are two broad populations. One is made up of neurons that conduct signals very slowly. Then there’s another class that conducts a little more rapidly—the class that produces a very discrete, localized, fast pain. Think of when you take a hammer and hang a picture and you hit your thumb. Initially, wow! It hurts right away. Then later it starts to really hurt. That’s the two classes of nerve fibers coming into play.

But there’s a whole other class of larger-diameter nerve fibers that conduct even more rapidly. They bring information from muscles and skin that’s of a non-painful nature: touch and joint position. When you bend your joints, they provide information. They definitely don’t respond to painful stimuli, so the question is, are they relevant to the experience of pain? The answer is yes, because in conditions in which they lose function, pain actually gets worse, because the cells not only have the capacity to carry information of a non-painful nature, but they have the capacity, through circuits in the spinal cord, to inhibit the signal sent by the pain fibers. People take advantage of that all the time without realizing it. When you burn your hand, usually one of the first things you do is shake it. What you’re doing is reflexively activating those other non-pain fibers, and what that’s doing is bringing in this inhibitory control system. You are reflexively taking advantage of what we now understand about the complexity of pain processing.

How can this understanding of the diversity of sensory neurons lead to new pain medications?

It used to be thought that all the pain fibers were homogeneous, but they’re not. They’re molecularly distinct, and that’s of pharmaceutical interest because if there is specificity in the biology of the pain fibers, then it might be possible to target these fibers selectively with drugs—a major goal.

“Our understanding of the molecular biology of the pain fiber in the peripheral nervous system is really one of the great hopes for drug development, because it turns out that there are specific proteins in those nerve fibers that can be targeted by drugs—hopefully selectively.”

Allan Basbaum, UCSF

The fact is, there are drugs for pain that are very good and effective—the problem is that they often have totally unacceptable side effects, because they are not specific for pain neurons. So patients are miserable, and they won’t tolerate the drugs.

But our understanding of the molecular biology of the pain fiber in the peripheral nervous system is really one of the great hopes for drug development, because it turns out that there are specific proteins in those nerve fibers that can be targeted by drugs—hopefully selectively. One of the most interesting proteins is the focus of clinical trials now. I mentioned that nerves conduct electrical impulses. They do it by moving sodium ions back and forth across the membrane of the nerve fiber, through ion channels. Several subtypes of sodium ion channels can be found in nerve cells throughout the nervous system and in heart cells. Local anesthetics work to block pain—and all sensation—by blocking sodium channels, but these can only be used locally, at the spot you want to numb. Otherwise, all the sodium channels in the heart and brain would stop working, which would be detrimental.

One particular subtype of these sodium channels is called Nav1.7. There is good reason to believe that targeting that channel specifically could produce remarkably selective pain regulation without side effects. The clue to that channel came from some rare individuals that have a mutation in the gene for Nav1.7, and they don’t experience any pain at all. Not experiencing any pain at all is really bad, because the warning signal is gone. But with a drug, you might be able to target the same channel and then regulate it so that you can reduce its activity when it’s overactive. That’s one of the holy grails: to be able to selectively target pain-sensing neurons. And because Nav1.7 is not found anywhere else in the body, the hope is that side effects would be reduced.

I think drugs aimed at Nav1.7 may be available within a five-year range. As the molecular revolution begins to identify more about the molecules that uniquely define cell types—and that’s possible now in a way that was not possible several years ago—that’s going to open up many new potential targets.

Pain feels like it’s coming from the body, but really it involves the whole nervous system, including the brain, doesn’t it?

We must not think of pain as an old telephone-line system where wires connect to the telephones, because then pain would be simple to understand: there is a telephone line up to the brain, and to treat it all you would have to do is cut the line. The pain system doesn’t work that way; it’s much more complex.

Pain has intensity and localization features. When you stub your big toe, that’s where the signal comes from—it’s localized, and it can be very intense or it could be mild. But it also has an emotional component to it, and without that, the signal is just sensory discrimination, but not pain. That information from the peripheral nerve fiber needs to access different parts of the brain. Some brain regions are involved in the localization—where is the stimulus? How intense is it? Other parts of the brain are involved in generating the emotional part of the experience. And these different parts of the brain interact to create what’s called the pain matrix. There’s no one particular area of the brain that you can just remove and get rid of pain, because pain is a much more complex experience. And just to make it more complicated, the extent to which a person experiences a condition as painful will really depend on the context of the situation.

The analogy I like to draw is to beauty. There’s nothing inherently beautiful in a particular painting that you see in a museum. Some people will look at it, and their heart will start to palpitate, and it might bring tears to their eyes. And they might be willing to spend a hundred million dollars for the painting. Someone else will look at it and say, “Pfft, it doesn’t do anything for me. I don’t get it.” The sensory input is identical, but the cognitive and emotional components are different in different people. So just as beauty involves these complex interactions, so does pain.

Pain serves as a warning signal, by telling us that the body is in danger from injury or illness. But sometimes there’s no detectable cause, or pain persists after something has healed. How does chronic pain differ from acute pain?

Acute pain—the “ouch” of a stubbed toe—is an easy one. We talked about how nerve fibers are activated. They conduct and send information that goes to the brain and you get “ouch.” And it is a warning signal. But chronic pain has absolutely no value whatsoever. Once you know you have a condition that’s causing pain—maybe the physician found a tumor, for example—you’ve received the warning signal. But why doesn’t the pain just go away? Chronic pain serves no purpose—it’s pathology.

“Chronic pain is not just long-lasting acute pain. It is input coming in to a pathologically altered central nervous system—in terms of the genes that are turned on or off, the nerve cell connections that are made, the brain circuits that are formed, and other circuits that might be lost.”

Allan Basbaum, UCSF

In most situations, chronic pain is a manifestation of ongoing disease, like arthritis where there is ongoing inflammation, so there is ongoing input to the central nervous system—and there is continuous pain. But there are other conditions where the damage is to the nervous system itself, and its only manifestation is chronic pain. That’s called neuropathic pain, and it comes about because the nervous system is altered. That’s an important feature that we now understand: chronic pain is not just long-lasting acute pain. It is input coming in to a pathologically altered central nervous system—in terms of the genes that are turned on or off, the nerve cell connections that are made, the brain circuits that are formed, and other circuits that might be lost. Some nerve cells might actually die. I refer to that reorganization as “maladaptive plasticity.” People use the word “plasticity” generally to think of good things happening, like when a person learns something new, or makes a memory; these are instances when new synapses form. In many ways chronic pain is similar, since the circuits and many of the molecules are the same. But with chronic pain, the long-lasting consequences are maladaptive—chronic pain serves no purpose.

If chronic pain is not working as a warning signal, is it a disease in and of itself?

Chronic pain is a disease state in the sense that the nervous system has changed. But there are very specific rules as to when something is called a disease. Chronic pain may not meet all the criteria, but when the only manifestation of the nervous system damage is pain—in my mind, it makes sense to call it a disease. For this “disease,” if you could treat the pathology, you could get rid of the pain. It’s therefore very helpful to think of chronic pain as a disease. This definition of pain also bears on the problem that there is very little philanthropic support for pain research compared to other chronic diseases, because people die in pain, not of pain. It’s not a fatal disease.

What are the remaining big questions for pain researchers?

One of the things that I’m dying to know is how pain is really processed in the brain. In other words, how do the signals generated by injury get interpreted by the brain to result in pain perception? One possibility is that some population of cells in the brain integrates and reads activity coming out of the spinal cord that says, “Aha! Now it’s pain.” We know that there are many nerve cells that respond to painful stimuli and send the message from the spinal cord to the brain. But how does the brain read that signal, and can we regulate that pattern of activity?

Another fascinating question has to do with so-called “labeled lines.” We know that certain sensory nerves transmit itch signals, while others carry heat pain, cold pain and so on. But does the output cell from the spinal cord that sends the message to the brain maintain that specialization? Or does it have the capacity to carry itch and various types of pain, and then the brain reads the firing activity of populations of nerve cells and says, “Aha! That was an itch stimulus,” or “that wasn’t a painful heat stimulus, but actually a cold stimulus.” We know that many peripheral nervous system nerve fibers selectively respond to stimuli, but the specificity seems to break down in the central nervous system. So there must be a “reader” somewhere in the brain, and I’d like to understand the location of that reader and how that reader works.

What would be your advice to someone living with chronic pain?

The best advice I can give is that you need to be seen by someone who really understands pain. That seems so simple to say, but the fact is most physicians go through medical school and residency with almost no training in pain management. As a result, they go to a book that says if a patient has a particular problem, give the patient a specific treatment, and if that doesn’t work, they don’t know what to do. But certainly a pain physician will have much more knowledge and a greater breadth of approaches that aren’t limited to just what the book says—maybe a combination of treatments or different approaches. So I think seeing the right physician is the most important first step. Also, try to find a good pain clinic—not all of them are good just because they call themselves one.