A New Lab to Study Pain and Itch: A Conversation with Steve Davidson

davidson-2Steve Davidson, PhD, is an assistant professor at the University of Cincinnati College of Medicine, US. Davidson is a pain researcher studying the neurobiological basis of pain and itch, and recently set up his own lab to pursue these interests. RELIEF executive editor Neil Andrews spoke with Davidson to discuss his path to pain research, the studies he is running in his lab, and what it is like to be a young investigator just starting out in his career. Below is an edited transcript of their conversation.

How did you become a pain researcher?

As an undergraduate at the University of New Orleans, I became interested in working in a science lab, and I joined one that was investigating opioid dependence in animals. I became very interested in pain through those experiments. I also read the work of the pioneering pain researchers Ronald Melzack and Pat Wall—my undergraduate advisor at the time was a disciple of Melzack—so I became very interested in their studies and in the history of the field. In general, I became very interested in how aversive stimuli in our environment affect behavior.

What did you do after college?

I went to the University of Minnesota, where there was a substantial focus on pain, to pursue a PhD in neuroscience. My work there looked at neurons in the spinal cord that send information up to the brain. These neurons are extremely important for perception, because without them—if, for example, the spinal cord is cut and these neurons are unable to send information to the brain—then the perception of pain, and also of itch, doesn’t occur.

Part of my work looked at where, in a region of the brain called the thalamus, these neurons project to and send pain signals, and how these cells functioned. We found that there were separate pathways, going from the spinal cord to the thalamus, that processed itch sensation produced by histamine versus itch produced by a plant called cowhage. This helps to explain why anti-histamines often fail to control some types of persistent itch.

After graduate school, I went to Washington University in St. Louis, and there I moved away from studying the central nervous system, which consists of the spinal cord and brain, to the peripheral nervous system. I studied dorsal root ganglion neurons, which are cells that transmit pain signals coming from the body into the spinal cord. Our focus was to look at the role of group II metabotropic glutamate receptors in these neurons; these receptors are molecules that are involved in communication between neurons. We were able to obtain pain-sensing neurons from human donors to study these receptors.

What questions about chronic pain are you interested in right now?

In the field of neurobiology, we’ve become aware of how dramatically the brain changes in response to various stimuli coming from the environment—sights, smells, and so forth. What I’m interested in now is how pain changes the brain, and in particular how long-lasting pain can change the way that neurons, synapses and neural circuits are organized in the brain.

For decades, pain scientists have been exploring pain-signaling pathways that go from the body into the dorsal root ganglion neurons and then into the spinal cord. Eventually this information gets to the brain, and I’m very curious about whether changes in brain neural circuits that are affected by incoming pain information can lead to the maintenance of chronic pain, even when the peripheral injury or trauma that caused pain in the first place has healed.

Is there a particular brain response to pain that you are interested in?

I’m especially interested in how pain produces negative emotional responses. I’m looking at changes in neural pathways in the brain that lead to these negative emotional responses, and whether or not these pathways are responsible for maintaining an ongoing chronic pain state.

One of the things I found as a graduate student was that there is a place in the thalamus, called the posterior thalamic nucleus, which receives many projections from spinal neurons, so we knew that this area of the thalamus was important in receiving pain signals. We’ve been looking at these neurons in the thalamus and they project largely to an area of the brain called the insula. The insula is a region that always seems to be involved in pain processing in human brain imaging studies, and is thought to provide a negative valance to painful information—that is, it’s an area that produces the feeling that pain is bad and unpleasant.

Earlier you mentioned that in addition to studying pain, you have also studied itch. Why would a pain researcher be interested in investigating itch?

At first glance, pain and itch seem to have a lot in common—they are both aversive sensations that occur somewhere on the body. It turns out that many neurons in the peripheral and central nervous system that signal pain overlap with those that signal itch—some neurons, for example, respond to both pain and itch, and some compounds cause both sensations.

There are some important differences between pain and itch, and people are able to discern the differences between them. And, pain can inhibit itch. But from the point of view of the nervous system, it’s been a challenge to tease apart which neurons might be important for itch and which ones for pain, or whether or not some neurons have shared responsibility for carrying information about pain and itch up to the brain.

Are you planning more studies on itch as your lab gets going?

Yes. We are looking at whether dorsal root ganglion neurons from human donors respond to agents that produce itch in the same way that neurons from animal models do. We’re also starting to look at whether conditions that lead to itchy skin, such as atopic dermatitis (a type of skin inflammation), can lead to increased activity of the neurons. By doing that, we hope to find whether there are factors that skin cells make that enhance the excitability of neurons that sense itch. Hopefully we could then obtain a therapy that affects those factors, in order to stop itch.

You mentioned using human neurons to study pain. Why is that important?

We wanted to use human neurons because of the low success rate that pain scientists have seen in translating their research into actual medicines that relieve pain. For example, doctors still use the same ibuprofen- and acetaminophen-type drugs that have been around for decades. Likewise, opioids are still widely used, and they have been around for thousands of years. Even though we’ve been able to find different ways to stop pain in animal models, we haven’t been able to create new medicines for people based on what we have learned from animals.

One of the reasons may be that the biology of the rodents that we typically use in pain research is different in key ways from the biology of humans. We’re interested in using human tissues in order to understand whether or not things that do work in rodent models will translate into humans, without first trying them in clinical trials, which are expensive and potentially can be dangerous.

How long will it take to translate some of the work you are doing into the clinic, to help patients?

There are approaches we are following in the lab now that could be translated in a handful of years. For example, we’re exploring molecules released by keratinocytes, the main type of skin cell. If we find a molecule that causes neurons that respond to itch to become very excited, we could very quickly try to block the functioning of that molecule. That might help to decrease itch, in conditions like atopic dermatitis, for example.

For the other project looking at the thalamus, we’re taking a longer view. As I mentioned, we are trying to identify neurons in the thalamus that are important for creating the negative emotional responses to pain and to shut those neurons down. But we’re still many years away from being able to do that in a patient.

You’ve been setting up your own lab—what has that experience been like?

It’s been a lot of fun, and filled with new experiences, but also very challenging. In graduate school and as a post-doctoral researcher, the goal was to come up with new ideas and critically review the research literature; there is no real training for starting a new lab. There are a lot of important decisions that need to be made on the types of equipment to stock in the lab and the people to hire, but I didn’t learn how to do that in a formal way. I had to rely on talking to other investigators in the field.

What is it like to be a young scientist now embarking on your own career as an independent investigator?

A lot of us feel very fortunate, because we know that many of our peers who we feel are our equals have been unable to start their own labs, for various reasons, some of which have to do with luck. There are certainly a lot of people who can fill additional roles as scientists, so I hear people say that we’re fortunate, and I agree.

There are some who think that too many people are pursuing PhDs, and that part of the problem is that there’s a glut of people being trained for positions that don’t exist. I completely disagree with that! Training as a scientist, as a PhD, gives you a set of skills that can be transferred not only to academic positions, but also to positions in government, journalism and other areas. In all of those cases, we need people with the right background and training to elevate public discourse about science.

If someone was considering going into science and becoming a pain researcher, what would you tell them about that path?

I would be extremely excited to talk to somebody like that. We need more pain researchers—we need more scientific researchers in general—and I would encourage anybody who wanted to become a pain researcher to follow that track. Certainly it’s a challenging path that takes not just hard work and intellectual resources, but also some luck. It also takes being able to interact with a community of other scientists who will value your opinions and ideas.

Many people talk a lot these days about how difficult the path is to becoming a pain researcher, especially in terms of securing funding needed to do the experiments. What are your thoughts about that?

The path is not unique to pain scientists. But pain science has actually benefited in recent years by being able to show that research in this field has the ability to help many patients. Other scientific disciplines, which are still absolutely critical to the continued success of science and medicine, are sometimes unable to make a very clear argument about how research in those disciplines will ultimately help lots of patients, and they have it worse than we do right now. But, all of us are talking about funding issues a lot more than we would like to be. We want to do more experiments and spend less time fishing for funding, but that’s part of what we have to do now.

Any final thoughts—for instance, are there things that you might wish patients with chronic pain, and the broader public, to know?

There are a lot of really talented people in the pain field who are working to solve extremely hard problems. Pain is a particularly difficult challenge because it is a subjective experience—each person has a unique experience of pain—and many different pathways in the nervous system are involved.

As scientists, we are all taking a long-term view of solving these problems, but because of the complexity of chronic pain, it’s not going to be easy. That may sound pessimistic, but I am actually very optimistic. We’ve learned so much, over the past several decades, about the neurobiology of how pain is processed in the nervous system, and decades are really not a long amount of time in the history of scientific progress. And each year, progress is accelerating. I’m very optimistic because we have so many ideas and new ways to potentially treat pain that we never even thought of before. Surely we’re going to have some successes and make a real difference.

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