At the IASP 2021 Virtual World Congress on Pain, to take place June 9-11 and June 16-18, the International Association for the Study of Pain (IASP) will present awards to honor the achievements of up-and-coming as well as more established investigators (these awards were originally to be presented at the 2020 World Congress on Pain in Amsterdam, which was canceled due to the COVID-19 pandemic). In advance of the meeting, PRF spoke with each of the winners. In this interview, we chat with Thiago Cunha, PhD, winner of the Patrick D. Wall Young Investigator Award for Basic Science. This award honors individuals who have achieved a high level of independence as scholars in the field of pain for basic science.
Cunha is an associate professor at the Ribeirão Preto Medical School at the University of São Paolo, Brazil, where his lab works to understand the cellular and molecular mechanisms behind pathological pain conditions, focusing on interactions between the immune system and the nervous system. His goal is to find new molecular targets for drug development. Here, Cunha speaks with freelance writer Stephani Sutherland to discuss his work on the neuroimmune contribution to pain, the cell types he focuses on, and much more. What follows is an edited transcript of the conversation.
How did you get into scientific research, and pain research, specifically?
I’m a biochemist by undergraduate training, and then I got my PhD in pharmacology. But I work at the borderline of neuroscience, pharmacology, and immunology. Professor Sergio Ferreira was a pharmacologist here in Brazil, and he made several important discoveries in the pharmacology field, especially in pain. I joined his lab about 2001, and I started my scientific career from there; he was my advisor.
I worked a lot on inflammatory pain, especially the role of cytokines and immune cells like neutrophils and macrophages. Then I decided to work on opioids. My PhD thesis was on the molecular mechanisms by which opioids can cause peripheral analgesia.
After a very short postdoc training, I found a position as a PI here in the Ribeirão Preto Medical School at the University of São Paolo, and started my own lab in 2010. When I got this position, I decided to start something more related to chronic pain, especially neuropathic pain.
We particularly use models of peripheral damage, like spared nerve injury and spinal nerve ligation models, and also models of chemotherapy-induced neuropathic pain. My lab is focused on how neuronal damage can change the phenotype of immune cells like macrophages and lymphocytes, and how immune cells can change the function of sensory neurons.
Is there a reason why you focus specifically on neuropathic pain?
One reason is the important medical need that we have in this area. Also, as a pharmacologist, since we don’t have specific and effective treatments for this type of pain, it’s very important clinically. And, in Brazil, we don’t have that much money to do research here. If you are broad in terms of an area that you are working on, you will need to spend more money. When you have a specific focus, maybe you can have more of an impact.
What cell types in the immune system are you focusing on, and how are they interacting with neurons?
We are now focused on two different types of immune cells. One is macrophages; we are trying to characterize one specific type that we are calling sensory neuron-associated macrophages. When you look at the sensory ganglia, which contain the cell bodies of sensory neurons, there are some macrophages associated with these neurons. But we don’t know the physiological role of these macrophages – nobody knows why they are there. We are trying to better understand if the macrophages could have a direct influence on neurons. After neuronal injury, we know that these cells expand, they start to become activated, they can proliferate, and they can produce immune molecules. We want to know how they can change neuronal function.
Another cell type that we are very interested in are dendritic cells, which may also play a role in neuropathic pain. There are no previous studies showing that dendritic cells play a role in this condition, but we are trying to show that. That’s part of our shift in focus to the adaptive arm of the immune system.
About the macrophages: You are saying they are associated with neurons in the dorsal root ganglia [DRG], but they can become activated by damage out in the periphery, far away from the cell body?
Exactly. This is the most interesting thing: How can these macrophages sense the damage that is far away from the DRG? Maybe it could be a direct activation; we don’t know exactly if there is a direct physical connection between these macrophages and neurons, such as gap junctions or other channels, that could directly activate the macrophages. We are testing this.
What needs to happen to get to new therapeutics? Will they be pharmacological agents aimed at immune cells?
Will the immune system be targetable by novel treatments? There is no doubt that the immune system and glial cells are very important for the induction of chronic pain, and we can use these findings to prevent the chronicity of pain. But when I think about the chronic phase of the disease in patients – not in a model – I’m not so sure that immune cells will be important for the maintenance of pain years after the damage. They could have an impact, but I’m not sure.
But in the chronic phase, what’s most important is the neuronal changes. We need to identify the processes that lead to the plasticity of neurons. What is tipping these neurons toward changing? We don’t know exactly. And it may not be so easy to reset these neurons. The big challenge is how we could reset the plasticity in the nociceptive system to recover from chronic pain. This is the most important question.
So the idea is that, in the maintenance phase of chronic pain, neurons and maybe the immune cells are at some new set-point, something different than they were. And, for neurons, that makes them hyperexcitable, and we don’t know what is maintaining that. Could there be ongoing communication between neurons and immune cells to keep that up? And maybe it’s different cells or different signals than those in the initiation of pain?
Yes, that’s right. This is why we are now moving to studying the adaptive immune system, because we know that this system has a memory, and these memories sometimes can be restored. These are hypotheses that we are testing. But when I am talking about immune cells like macrophages or even microglia, it is becoming clear that microglia are more important for initiation and other processes. We also have some projects now looking at astrocytes.
Another point is, regarding other types of chronic pain such as chemotherapy-induced neuropathic pain, you know exactly when you are giving the chemotherapy. So perhaps we can use this knowledge to prevent chronic pain. In my view, it’s better to prevent it than to try to treat it.
What are some of the biggest challenges in developing new pain drugs and studying pain?
One problem is the models. Most of the models we have, especially in mice, are very short-lasting models. It’s difficult to predict when this is really a chronic pain condition in mice, which are different from patients. It seems that now we are improving behavioral testing. And we’re moving away from just testing sensation, by better evaluating what is going on in terms of psychological changes in the animals, using different novel tests that we can apply to the field. We are moving in the right direction, but of course it takes time to translate.
What keeps you motivated to do this difficult research?
It’s not an easy field, and nowadays the students are not so motivated to do behavioral experiments – sometimes it’s kind of boring! They are more motivated to do molecular work or imaging, but at the end of the day, testing the behavior is the most important experiment.
What’s motivated me? I think it’s the problem of chronic pain. When we publish a paper and the media covers it, and then sometimes patients come to us asking for a novel treatment, they say, "I’m suffering from chronic pain." This challenge to solve a human problem is what motivates me, and, of course, to find new drugs to treat it.
You mentioned your advisor, Sergio Ferreira, who passed away in 2016. Do you have other scientific heroes, whether in the pain field or outside?
I have two important mentors. Sergio, of course, was very important, especially because he always asked us to concentrate on the ideas. I try to follow his advice.
Another very important scientist that impacted my career was Fernando Cunha, who also worked with Sergio. People ask, "Is he your father?" No, we have the same name, but he is not my father. Fernando is a hard-working scientist. He loves science, and he was one of the scientists who gave me the incentive to keep on track, to work hard, and to be confident in my work, because sometimes I don’t believe in myself. Sometimes you need someone to say, "You are doing great work."
Congratulations on winning the Patrick Wall Young Investigator Award. What’s your long-range vision, and what do you want to accomplish?
I want to apply my knowledge of the immune system to neuroscience. I’m planning to do a sabbatical to learn electrophysiology, because I think electrophysiology can help a lot to analyze neurons’ functionality. Another idea is to use human induced pluripotent stem cells in the lab and do electrophysiology on these cells.
Maybe in 20 years we can have one molecule or one compound that can be used to treat chronic pain. My wish is to participate in or to discover something novel in terms of analgesic drugs. This is the dream, of course, because it’s not easy. There are a lot of people trying to do that. But we need to keep trying.
I’m very happy about the award, of course. I was not expecting it. For a Brazilian scientist to receive this important award – it was a surprise. And I will be here, keeping on in this pain field.
Stephani Sutherland, PhD, is a neuroscientist and freelance journalist in Southern California. Follow her on Twitter @SutherlandPhD