The fundamental discovery was the identification of a protein that is expressed in a sub-population of nerves; that is, an ion channel protein that can be activated by capsaicin. That was one part of it. Another big part was that we showed that this protein is restricted to just the nerves involved in pain sensation. The real kicker was that this same protein could also be activated in the absence of capsaicin simply by increasing temperature into the painfully hot range. So it’s temperatures above about 42 degrees Celsius, roughly 108 degrees Fahrenheit, that will activate it, and that is the temperature where we start to feel pain on our skin.

What we reasoned was that no one had ever identified capsaicin inside the body, so it seemed unlikely that nature had put this channel in our pain-sensing neurons just so we could enjoy eating spicy foods. It seemed more likely that capsaicin, when it was causing pain, was essentially doubling for something that would normally provoke a sensation of pain. So what we did was screen through a number of stimuli we knew were capable of causing pain and also stimuli that had already been shown to activate sensory neurons when removed from the animal, and looked at in a dish. A year earlier, two different groups had shown that if you take the sensory nerves that normally innervate a rat’s skin and put them in a dish and record from them electrically, you could activate a sub-population of those nerves by increasing temperature. So our group did the same thing with this molecule we had recently isolated. We were able to express it in a cell line that normally didn’t make it. And not only did these cells become sensitive to capsaicin, but they became sensitive to heat.

I think it’s a couple of things. One is that this provided—I think for the first time—a molecular handle on that population of neurons involved in pain sensation. It gives you a way of marking those neurons, of specifically manipulating those neurons. So that’s one thing. I think there are two other features that made this stick in people’s minds. First is that the molecule itself looks like it’s very important for pain sensation. If you remove that molecule from mice, they are not only completely insensitive to capsaicin, but also less sensitive to painful heat than normal mice. So the capsaicin receptor itself represents a target you can go after in developing drugs that can combat pain. The final thing is the recognition that this particular molecule could act as essentially a molecular thermometer. That led our lab and others to look for related molecules that could be involved in temperature sensations over other ranges. We’ve now found a whole family of these molecules; there are at least six of these molecules expressed in mammals that act as temperature sensors, activated over different temperature ranges.

That is a question to which we still don’t know the answer. We strongly suspect they do. So far, we have been removing them from mice one by one, but we haven’t yet found one that’s indispensable for maintaining normal body temperature. Out of the three or four knocked out in mice so far, those mice have all shown normal body temperature for the most part.

In a couple of interesting ways. One is that with the molecules in hand now, people have been able to understand in much greater detail how it is we become more sensitive to heat when tissues are injured. If you have an infection or inflammation, your skin becomes more sensitive to heat or touch than normal. It turns out that this capsaicin receptor is very important for the enhanced perception of heat that happens after injury. Work from a number of laboratories has now led to the understanding of some of the molecule details of how this happens; how the protein itself gets changed, and how the expression level gets changed. It gets modified in ways that make it more sensitive. So our understanding of how injury and inflammation sensitize our nervous systems to pain has really moved forward. Another thing that we recognized by looking at other related proteins is that heat and cold are actually sensed by structurally similar channels, probably in biophysically similar ways. And finally one of the things we’ve been most interested in is that it’s not just nerves that make these temperature-sensitive channels, but some of the epithelial cells that line our skin or internal organs also make some of these channels. There’s growing evidence from our lab and others that these skin cells are probably cooperating with nerves to help us perceive temperatures.

We’re not entirely sure yet. The channels that are tuned to the warm temperature range, say 30-42 degrees, are very highly expressed in skin cells and when those skin cells get exposed to warmth, the channels get activated. What we presume is going on is that the skin cells are releasing chemical substances that are then detected by the nerves that come very close to them. That’s the model right now. We don’t have absolute proof that that’s what’s going on. This is work from several different laboratories. If you remove those channels expressed in the skin cells, you’ll see the animals’ perception of warm temperatures change.

There certainly has. Not long after the discovery, a number of pharmaceutical companies began looking for chemicals able to block this receptor. The consequences of the discovery that I discussed before were mostly from the standpoint of a research scientist. But from the standpoint of medicine, one of the most important things, with this channel now in hand, this capsaicin receptor in hand, is that companies were now able to set up very easy screening protocols to see which compounds might be able to block this channel. So they’ve been doing that, and a number of promising compounds have come out of that research. In fact, a recent study just came out a couple of months ago, in which one group reported that they could block the pain associated with an experimental form of bone cancer by administering a blocker of the capsaicin receptor.

I think one of the big questions is given that there are multiple sensors for heat and warmth, how is the body using these different sensors in different ways? They seem to be expressed in different cells, some in neurons, some not, and they seem to be responsible for different aspects of temperature sensation. But we still don’t have a clear picture of how the body is using them all to sense heat and pain. That’s one question. Another is that we have much more limited information on how mechanically evoked pain is perceived. If you hit your thumb with a hammer or poke yourself with a pin, how is that pain perceived? How does that pain caused by pressure evolve? Does it involve the same class of proteins or different classes? The early indication suggests maybe some of these same channels are involved.

Our focus isn’t exclusively on pain now. I would say that the one overriding theme of work in my laboratory is temperature. We’ve been involved in both pain-related and non-pain-related aspects of temperature perception, including the kind of questions we discussed earlier such as how body temperature is regulated, things like that. I guess I never set out to focus on any one particular area. I figured that I would just let the answers tell us where to go next. This was a lesson that my previous advisors taught me, and it has certainly worked well so far.