Editor’s note: Seven early-career pain researchers took part in the PRF Correspondents program during the 7th International Congress on Neuropathic Pain (NeuPSIG 2019), which took place May 9-11, 2019, in London, UK. This unique science communications training program provides participants with knowledge and skills needed to communicate science effectively to a wide range of pain researchers, and to patients and the broader public. In addition to blogging and writing summaries of scientific sessions, the Correspondents also conducted interviews with plenary speakers and other researchers at the meeting. At NeuPSIG 2019, PRF Correspondent Liam Peck, an MB-PhD student at the University of Oxford, UK, spoke with plenary speaker Rohini Kuner, PhD, for an interview.
Kuner is professor of Pharmacology and Toxicology, chair of the Department of Molecular Pharmacology, and director of the Pharmacology Institute at Heidelberg University in Germany. Her research focuses on molecular, cellular, circuit, and organismal mechanisms of neural plasticity in chronic pain, with a particular interest in a reverse translational approach to pain research. In this interview, Kuner discusses her career to date, her recent research on cortical oscillations in pain, what it was like to win the Feldberg Prize, and more. Below is an edited transcript of the conversation.
I’ve been fortunate enough to hear you speak a number of times recently. One thing that’s impressed me is that you have always spoken about something completely different each time. How do you manage to maintain such an expansive program of work?
The honest answer is that I tend to get very bored with being stuck with one topic. Science is all about curiosity and excitement about what you’re doing. So I work on things that interest me and questions that I think are important and relevant. Sometimes these are quite far apart from each other, but if they’re important and I feel that our group can make a contribution, then we go for that.
Having said that, of course, the group is divided into a few smaller units where we do have a focus. So for each of our units, be it cancer pain, diabetic neuropathic pain, or brain circuits, we have about four or five people working together. So there is some coherence, and the main aspect that we try to go for is translational research. In our case, it’s reverse translation—we try to understand what’s going on in humans and then model that in animals.
If you had to pick one of your many contributions to pain research, which one would be your favorite, and why?
That’s a trick question! I would still go back to my very early days when I had established my group. We were working on the plasticity of glutamatergic synapses in the spinal cord, and we uncovered a number of new molecules and principles that lead to both functional and structural plasticity of synapses. This includes the finding that calcium-permeable AMPA receptors are key molecules that trigger plasticity in the spinal cord; this was the first Neuron paper that my group had after it was established. Along with that, thereafter, was the discovery of Homer1A as an endogenous brake, also in glutamatergic synapses, in terms of both function as well as structural plasticity of synapses; this was published in Nature Medicine in 2006. These are still my favorite contributions.
In the end, it does all come down to synapses, as the building blocks of memory and chronic pain. So even though I have branched out more into higher-level circuits and systems-level analyses, I would still love to combine that with very basic neurobiological mechanisms.
What lessons have you learned in transitioning from studying the periphery to examining the cortical representation of pain?
What I’ve learned is that I’ve always enjoyed looking at the periphery—and I still do—in terms of neurobiological mechanisms because that is the origin of pain, of course, in many conditions.
I’ve also begun to see that things I always assumed to be peripherally maintained, such as diabetic neuropathic pain, may not be so. There might be initial triggers and, of course, there is ongoing neuropathy and damage in the periphery, and perhaps also in the spinal cord, which has not at all been looked at; you can have spinal plasticity, which then also triggers brain plasticity or brain contributions. But in the end, whether a particular input or plasticity process leads to chronic pain or not depends upon whether the cortex goes with it and the limbic centers come into play. And I’ve learned that there is a major distinction between sensory aspects of pain and affective aspects of pain; the affective aspects can be equally important, if not more important.
I’m learning more and more that many diabetic patients also suffer from dementia, loss of memory, and depression, in addition to pain. So the chronicity of pain could, indeed, come from cortical plasticity, as with those other comorbidities. What I’ve come to understand is that you can’t study pain in isolation. You have to study it with its comorbidities, and very often these are similar circuits or highly intertwined circuits that mediate them. In the end, it’s not just the pain but the comorbidities with the pain that lead to deterioration of quality of life.
Do you think more people should try to bridge the gap between the peripheral and central nervous systems?
Yes, absolutely. It’s just as hard as trying to understand how happiness comes about, which is sort of the opposite of pain, but I think it needs to be done.
It’s incredibly challenging because the same brain centers affect many functions, be they emotional, cognitive, or motor functions. The motor functions in particular are very bothersome because all of our readouts so far are based upon motor activity—this is what makes it very, very difficult to discern the brain regions involved in the sensory pain response versus those involved in, for example, limb withdrawal. But I’ve learned that even though it’s difficult, one has to try to forge ahead and learn—it is important to get down to the neurobiological basis.
Recently, you showed that there are cortical oscillations associated with withdrawal reflexes and ongoing inflammatory pain states. How do you reconcile that with previous observations that these reflex responses are still persistent in, for example, decerebrate rodents?
What happens a lot in science is that studies get cited in a secondary or a tertiary manner without going back to the primary work. To be very honest, I have not seen a single paper on decerebrate animals that has convinced me that this withdrawal behavior is entirely devoid of contributions of the brain. I have gone back to the original literature, and it has not convinced me.
So are withdrawal reflexes a real readout of pain?
I think so. First of all, you can study behavior in patients by using von Frey application, for example, and you can see that subjective reports from patients do quite accurately match objective stimulus intensity. So I absolutely believe that withdrawal assays do lead to pain rather than just reflect a spinal reflex.
It is very important to study all kinds of behaviors and not just sensitivity to a particular mechanical or thermal stimulus. I’m very happy that there are more and more behavioral tests coming out. We are also trying very hard to contribute to this. At the same time, I believe a von Frey stimulus is perceived to be noxious because you see also that animals actively walk away from it; it’s not just a reflex.
In any case, if you go with an open mind and look when brain activity comes about in response to such a stimulus, what is absolutely clear is that it happens before the motor response. If it was something secondary, independent of the behavioral response, then brain activity need not have come earlier.
At the least, the brain has an opportunity to decipher that there is an input before the behavior is formulated. Whether or not the brain now contributes to that is something I cannot say. But at least in our case, as shown in this study, we do see that the potentiation of nociceptive behavior by gamma oscillations in the S1 cortex does come about by recruitment of descending facilitation. I do believe that, both via facilitation as well as inhibition, the brain does play a very important role, at least in modulation of these responses that we think are purely spinal.
In that paper, you used some intricate optogenetic techniques to drive cortical gamma oscillations. What techniques or concepts in pain are you really excited about for the next five or ten years of research?
I always have to watch out here because I’m a pharmacologist, and as a pharmacologist, I should be talking about drugs and new targets. Indeed, as you know, I do work on neurobiological processes and believe very strongly in molecular and cellular neuroscience, and their ability to yield new targets. However, what I have also noticed is that there is so much redundancy, in terms of signaling pathways and especially molecular mechanisms, so one needs a more holistic approach. I’m becoming more and more convinced of modulatory methods based on brain activity or neuronal activity rather than targeting single molecules or single pathways.
I hope that our research will make a contribution to improving such modulatory methods. There is conditioned pain modulation, there are all sorts of brain stimulation methods such as transcranial magnetic stimulation, and there is also direct or alternating current stimulation. One can use these methods at the level of the spinal cord as well. From what I see, in very refractory cases of neuropathic pain, spinal cord and brain stimulation hold a lot of promise.
However, the mechanisms are not well understood. In particular, if you go back to the original studies, there is a huge amount of variability, and this is why there is still not much confidence in these methods. What I hope is that we, as animal experimental scientists, will be able to decipher the exact cellular and circuit mechanisms by which these modulatory and stimulatory methods work. Then we could further design and improve these methods such that they are more specific, and more efficacious.
Perhaps we will not have a magic formula that applies to all sorts of pain. We see very clear differences with respect to brain circuits when it comes to inflammatory versus neuropathic pain, for example. And neuropathic pain of different origins has different mechanisms. So we have a lot of work to do in the future. It’s very exciting because I see that clinicians are very open to these kinds of studies. They do fully recognize now that these new methods in experimental rodent analyses actually can be very useful in delivering mechanistic insights for their kind of research.
Earlier there was a strong divide between clinical scientists talking about imaging, transcranial magnetic stimulation, or neuromodulation, and people who talk about TRP channels, sodium channels, and so on during sessions on molecular and cellular neuroscience; these are two different communities. But what I’m very excited about is that these communities are coming closer and closer together and are making a big contribution. Our work is highly influenced by clinical findings, and I’m really happy that clinicians do take our findings very seriously.
Last year, you were awarded the Feldberg Prize, given annually to one German and one British scientist for outstanding contributions to research. This must have been a very proud moment for you. Will international collaboration in science prevail over political distractions such as Brexit, for example, given that we’re here in the UK today?
Absolutely. Politicians come and go, and upheavals can happen. But the hearts of people are joined, and these bonds that we have will not be broken. I’m 100 percent sure of that, and we scientists can make a huge contribution towards maintaining and strengthening our ties. Great Britain is the home of some of my best friends in science, people whom I hugely admire like Irene Tracey, David Bennett, Steve McMahon, and several others. I will continue to have the best of relations and also a huge amount of exchange as ever. I’m 100 percent sure that these artificial boundaries, if they do succeed for a short time, will not succeed in keeping us apart.
You mentioned Irene Tracey, who preceded you in receiving the Feldberg Prize. You are both heads of your departments and emblems of success for women and mothers in science. What more can we do to help young women in research succeed and become independent senior scientists?
Five years ago, I would have said we need more programs with role models, more programs for networking, and more programs where young women are emboldened to combine family and research. All of that has happened; there is a tremendous level of advance and success. My feeling is that this has reached a plateau, and the bottleneck is not the networking or having role models—it’s having jobs. Now the next step will be to create real, tangible opportunities, and to stop talking about emboldening women in science—they are already emboldened. But if you don’t have a position, there’s very little you can do.
This is where I find that very little is being done in terms of creating actual fellowships and grants that are tailor-made for researchers at this early-career stage. If I were in a position where I could influence these processes, then I would suggest creating such programs that young women in science, especially those with families, can utilize. We have a few in Germany and a few at the university level, and I’m sure the same is true for other countries. But maybe here is where a contribution could be made by associations such as the IASP. They have several grants, which I like very much, for young scientists. But perhaps they could also make a statement along these lines by supporting young women in their early independence by giving them tangible support in terms of grant money, so that they can stand on their own feet and create their own path.
We began by talking about your diverse interests in science. Does this apply even outside of science?
Absolutely. I’m very interested in languages, and I read a lot. I’m interested in gardening, too. I have a huge park, actually; I can’t call it a garden. It has vegetables and animals, all sorts of flora and fauna—ducks, fish, dogs, and cats. I’m also interested in cooking. Every time I go to a new place, I try to learn at least one dish, what I consider as soul food. That’s absolutely my pastime.
Liam Peck is an MB-PhD student at the University of Oxford, UK.