Dr. Ronald Dubner has a long and distinguished career in pain research. He is credited with establishing the first interdisciplinary pain research team at the NIDCR during the early 1970s, and his studies have helped to lay the groundwork for defining the anatomy, physiology, pharmacology, and genetics of pain. Dr. Dubner, now a scientist at the University of Maryland in Baltimore, recently talked with the Inside Scoop to discuss the past, present, and future of pain research.
I've heard many people say it's a good time scientifically in pain research. Do you agree?
Oh, absolutely. I think it's an outstanding time in pain research. We have so many new tools and approaches to study pain. What we need to do is to begin to talk to each other more within the various disciplines.
How long have you studied pain?
I've been in the field since 1968.
If I remember correctly, that was around the time that the "gate control" theory of pain was proposed.
Correct. Ronald Melzack and Patrick Wall published the theory in 1965.
Melzack and wall proposed that nerve impulses from an injury don't travel directly to the pain centers of the brain, as everyone believed at the time. They reasoned that the impulses must first pass through the spinal cord, where other nerve cells act as gates that modulate the signal, either blocking the impulses or swinging open like a door to allow them to pass to the brain.
That's right. When Melzack and Wall first proposed the gate-control theory, it completely energized the field. Although some of the basic mechanisms that they proposed turned out to be incorrect, the theory nevertheless provided a broad framework from which investigators could approach the inherent complexity of pain with its multiple variables.
Just as importantly, the theory prompted clinicians to talk with basic scientists about the biology of pain - and vise versa. This merging of the disciplines - or, what we call today, interdisciplinary research - led to the beginnings of an international association for the study of pain. Thereafter, organizations of similar interdisciplinary structures arose throughout the world, including the United States with the formation of the American Pain Society. All of this activity was enormously important, when you consider that clinicians at that time tended to avoid patients who complained of chronic pain.
For instance, we didn't know then that there were specialized pain receptors that signal tissue damage. There had been some suggestions that it might be the case, but we really didn't know. We also didn't know anything about how the brain modulates the sensory impulses as they arrive from a site of injury. And, we certainly knew nothing - NOTHING - about the changes in the nervous system that result from the barrages of information that emanate from the periphery after injury. These fundamental discoveries now represent the hallmarks of pain research.
Let's run through the three hallmarks again?
Sure. The first is understanding the sensory coding of signals related to tissue damage. How are these messages encoded in the periphery and relayed to the spinal cord and higher centers? Two, understanding the role of descending modulation and its effect on this coding mechanism. In other words, how does the brain inhibit or facilitate pain signals based on our previous experiences of pain, how we feel about pain, and how it influences our behavior? Three, understanding what we call "plasticity." How does the barrage of sensory inputs cause changes to take place in the connections of the nervous system?
Plasticity is an extremely important mechanism for brain function in general, not just in terms of pain. Others have studied it related to learning and memory, and there are strong parallels between the changes in the nervous system from a persistent sensory barrage due to injury and those that take place during learning and memory. It suggests that pain is a very, very relevant input into the nervous system that has strong survival potential.
Given these guiding principles, what are some of the major research questions today?
We need to get a better handle on the role of genetic variability in pain. What are the most common variations, for example, in the genes that encode the mu-opioid, kappa-opiod, and the other myriad receptors involved in the transmission of pain? These variations underlie, to some extent, the long-recognized differences in how people experience pain and influence their responses to common pain medications.
Another important question is how do the various pain receptors function in the peripheral target tissues, such as skin, muscle, and the deep tissues? We also need to learn more about the receptors and their mediators in the central nervous system in transmitting information about pain and modulating pain. We have to learn about them not only in the nervous system, but also as modulators released from tissues and blood, which affect the whole system. We also need more understanding of the hypothalmic-pituitary-adrenal axis in this whole experience of pain. That is, how does the brain's hypothalmic region influence the release of adrenal hormones that influence pain? All of these areas need more elaboration.
With the idea that discovery and technology development go hand in hand, which types of research tools will be required to enable pain research to move forward?
We need to take advantage of imaging and genetic tools to understand the specific roles of various sites within the brain that are important in the experience of pain, particularly the forebrain. I mention the forebrain because pain is more than just a sensory phenomenon. It's an experience that involves, not only what we perceive, but how we interpret it. And we need to keep that in mind. Pain goes far beyond the actual transmission of sensory signals.
Historically, why is it that pain research has sort of fallen through the cracks when it has such a central place in the human experience?
In some sense, though I hate to admit it, you are right. People have thought of pain too much as a symptom. What we're learning now is that pain, in fact, is a disease. This has been suggested for several years, and I think the evidence is quite strong on this point today. For instance, we know that tissue injury leads to remarkable changes throughout the body. It has effects not only on the nervous system, but also the immune and hormonal systems.
By considering pain to be a symptom, science has in a very reductionist way avoided it. Many scientists have have assumed that, if they identify the root causes of various diseases and cure them, there won't be any more pain. But what I'm saying is pain in itself can be the disease. You're always going to have people in pain, and the pain is going to produce changes in various functions of the body. Therefore, we need to look at pain early on and not only focus on curing the underlying disease.
We need to listen to biology, not impose our ideas on it.
That's right.
The vast majority of pain medications are, in actuality, different iterations of opioids and aspirin that target the same, well-known pathways - that is, the routes in the body that molecular or sensory signals travel. Are there other promising pathways involved in pain that are awaiting discovery?
There are tremendous opportunities now with the cloning of a number of new receptors in the periphery that signal tissue damage and carry information to the nervous system. There's a tremendous opportunity there to develop very, very new agents that might play important roles.
As we learn more about how information within a cell is processed, or, more specifically, how information related to tissue damage produces changes in the nervous system, we can begin to learn about the plasticity that is so important in pain. By so doing, we'll also derive new agents to control pain. For those who cannot now get relief from existing pain medications, we need to understand what the underlying mechanisms are of their chronic pain. What is it that remains changed, even after the site of injury is healed?
It's expensive to define all of these pathways, isn't it?
No, I don't think it's that expensive. It's not any more expensive than understanding any other areas of the brain or neural mechanism.
But it's expensive for industry to invest the research money without the guarantee of striking paydirt.
Well, that's where the partnership comes in. Industry needs to partner with government; it needs to partner with academic institutions; and, government and academia need to seek out the substantial resources and expertise of industry. In short, everybody needs to work together to advance the science. And, it's not just wishful thinking, because there is a tradition of all three working together in the pain field that dates back to the 1970s and the advent of interdisciplinary approaches in pain research.
Given this interdisciplinary tradition, which other disciplines might be beneficial to pain research today?
I think we need to work not only with chemists, but with physicists and engineers. There's just such a plethora of approaches that one can envision to manage pain and increase quality of life for patients in pain. I often say that to study pain is to understand the brain. If you study pain, you better understand the underlying mechanisms of brain function.
Scientifically then, it's really about making the investment and just going after it?
I think so. This is a time when there are budgetary concerns all over - government, universities, industry. There are great concerns about the cost of developing new agents. I think what the future requires is a partnering amng the components of our intellectual enterprise who are interested in improving the quality of life of people in pain. I think that's where we should be going. I believe we are headed in the right direction, and the coming years should be extremely exciting in pain research.
October 2003