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David Julius knows the pain. Professor of Physiology at the Faculty of Medicine at the University of California at San Francisco, he has devoted his career to studying how the nervous system perceives it and to detecting chemicals such as capsaicin, the component that gives the chili pepper heat, activating pain receptors. Julius received a ground-breaking $ 3 million life sciences award on Thursday for "the discovery of molecules, cells, and mechanisms that underlie pain."
Julius and colleagues have shown how cell membrane proteins called transient receptor potential (TRP) channels are involved in the perception of pain and cold or cold, as well as their role in inflammation and inflammation. Hypersensitivity to pain. Much of his work has focused on the mechanism by which capsaicin exerts its powerful effect on the human nervous system. His team has identified the capsaicin-sensitive receptor, TRPV1, and has shown that it is also activated by heat and inflammatory chemicals. More recently, he revealed how the scorpion venom targets the TRPA1 "wasabi" receptor. Drug developers are currently investigating whether these receptors and others could be targeted to create nonopioid analgesics.
In addition to his discoveries about pain, Julius discovered a receptor for serotonin, a chemical that signals the brain. He is also interested in other types of sensory reception, such as infrared detection in snakes and electroreception in sharks and rays.
American scientist spoke with Julius about his work on understanding pain, why we need it, and how it can go wrong.
[[[[A modified transcription of the conversation follows.]
How did you start to study pain?
When I did my postdoctoral work, I became interested in the nervous system. I wanted to understand how neurotransmitters like serotonin work in the brain and what the receptors for these neurotransmitters look like. using genetics and molecular biology to try to understand this. I'm really fascinated by this whole idea of popular medicine and health, and how scientists have exploited natural products to understand physiology. I was interested in issues such as how hallucinogens work – how people discover things like peyote and use them ritually. The chemists, of course, had discovered the active ingredients and how they work on the nervous system. And I've just been really fascinated by this whole approach, where people are studying human behavior and integrating it into the field of chemicals, and then using these chemicals as clues and beacons to understand how the nervous system works. That eventually led me to wonder how some of these agents in our environment are causing pain …[chemicals] like capsaicin and wasabi. And so, for me, it was a bit natural to want to use natural products to understand the nervous system.
I've heard that you had the idea of studying capsaicin while you were at the supermarket. How did it happen?
[Laughs] I was looking at these shelves and shelves of hot peppers and chili extracts (you know, hot sauce) and I thought, "It's such a big problem and so much fun to watch. I really have to be serious about it. My wife was in the hallway – she's also a scientist – and she looked at me and said, 'What are you doing?' And I said, "I'm really frustrated. I really need to understand how we can solve this problem. She said, "Well, stop hacking. Why do not you go there? It's like everything else: you need the right time, the right people, the right technology. And [Michael] Caterina, who was in my lab at the time, is the one who said, "Yes, I'm going to take up this challenge." And he did a fantastic job. And so, you know, science is like this: at the right time, things come together.
You and your colleagues have discovered that capsaicin activates a receptor called TRPV1. How does this help us feel the pain?
It is a protein found on the surface of nerve cells. It is found mainly on the nerve cells involved in the sensation of pain. And it's an ionic channel that, in essence, forms a "donut" in the [cell] membrane, where the central hole is closed until something active. And then the ions can flow from outside the cell to the inside. (The ions we are talking about here are mainly sodium and calcium ions.) When this happens, it creates electrical currents in the cell and triggers the triggering of the potential for action. So, it sends the electrical signal from the periphery – say, your lips or your eyes, wherever you smell the hot pepper – and sends the signal to the spinal cord. And then, in the spinal cord, these neurons (what we call primary afferent sensory neurons and nociceptors), they send the signal to a second neuron in the spinal cord. Then, through a relay of neurons, it ends up being transported in the brain to centers where you perceive it as something harmful and painful.
What is interesting about this ion channel is that it is activated by heat; it plays a role in our ability to detect hot things. This is the kind of information convergence that a chili mimics a thermal stimulus. But the channel does not only detect heat; It also detects agents that our body makes in response to inflammation.
Why do we have the ability to feel pain?
One of the interesting aspects of pain, of course, and we all know it, is that when there is injury, whether it's tissue injury and inflammation or injury from the nerve fiber itself, the pain is accentuated. And the reason is, presumably, to improve protection: when you wiggle your ankle, you must know that you have done something wrong to protect it and let it heal. People who lack this ability, for example, people who have [a common complication of] diabetes or people with leprosy [Hansen’s disease]They have no sensation in their extremities. If they hurt themselves, they have a foot ulcer and do not know it, they do not know how to protect themselves and the virus is infected. So all this improvement in pain sensitivity, in its best form, is there to protect us and tell us that we need to protect the site. Of course, the problem is that sometimes it gets out of hand. And then we have persistent or chronic pain syndrome.
How can we exploit the capsaicin receptor and others to treat pain?
TRPV1 does not only detect heat; It also detects many chemicals produced during inflammation. The chemicals act on these pain-sensitive nerve fibers to enhance their sensitivity to elements such as temperature, touch, and other chemicals, as part of the protective response. This TRPV1 channel can detect many of these different inflammatory agents and thus contributes to the increased sensitivity of the nerve fiber in the context of an injury. And this is the main reason why people are interested in these types of molecules as potential sites for painkillers: because they contribute to the hypersensitivity to pain in case of injury. So you can imagine that in situations such as arthritis or inflammation of the bladder or gastrointestinal inflammation, with the production of many of these inflammatory mediators, the TRPV1 and other [channels] are important players in resetting the sensitivity of the nerve fiber in the context of injury. What you want to do is reduce the pain when it is pathological. But you do not want to eliminate acute and useful pain, because you do not have a warning system, right? It's a bit of what people want to achieve. And the idea is that you may be able to block the ability of these inflammatory agents to sensitize the nerve fiber by targeting objects such as TRPV1 and other similar molecules, but try to do it in a way that saves the function normal protection of the receiver. way of pain.
Could these pathways lead to an alternative to opioids? And how far is it?
It's a good question. I do not work with pharmaceutical companies or anything, so I can not tell you where the current state of affairs is. However, drugs have been developed for some of these chains, such as TRPV1, the one that has been identified for the first time. Some models of pain in humans have worked well at least modestly, but they have had what I would call targeted side effects: they reduce the ability of patients to detect excessively hot objects. So [pharmaceutical companies have] fears that people will get hurt by drinking hot coffee, for example. And the other thing is that, probably because they change your feeling of temperature sensation, people at least temporarily report a little fever. Until now, I have not seen any drugs in which you can enter. [a pharmacy] And buy. But drug development is a long process and I hope that some of the molecules we have discovered or worked on will eventually be targeted by new analgesics that are not opioid analgesics.
Opioid receptors are expressed throughout the nervous system: they are expressed in the brain, in the spinal cord, in pain, sensory fibers. Thus, opiates have many other effects on the nervous system that cause things such as respiratory depression, which leads to constipation, that affect cognitive areas. So you have things such as tolerance and dependency. So, the initial goal of the work that we have done, and the approach taken by us, and others on the ground, is to focus on the peripheral nerve fibers, such as the skin, and other places dedicated to the detection of pain reactions, with the idea that if we can identify the molecules that are more selectively expressed on these sites, the side effects of the drugs will be fewer.
Besides pain, you have also studied other sensory abilities, right?
Right. We are generally interested in sensory systems and in understanding what the sensory system does as a whole, not just through the path of pain. They allow your brain to generate an internal representation of the outside world. But what I find really fascinating in sensory systems is that different animals see the world differently. We have examined [infrared sensing in] because we thought, like other people, that this is related to the feeling of warmth – and because it is close to what we are working on, in terms of understanding the mechanisms of the sensation of pain. More recently, some guys from my lab have been working on electroreceiving mechanisms [sensing electrical fields], which are found in aquatic animals such as rays and sharks. People have studied these animals and identified the fact that they use these systems, such as infrared sensation and electroreception, for many years and have done some fine work on physiology. What was not so much addressed is really to understand the molecular basis for that. And now, there are so many tools that we can use, such as DNA sequencing and RNA sequencing, where you can really try to make the link between the molecules and physiology. So it's a little where we intervene. We have taken these molecular tools and revisited these very beautiful studies to try to define a molecular framework for these behavioral and physiological systems.
What do you intend to do with the prize money?
I think I will continue to do what I do. I like to give money to the community – I really like to support the arts, music and science education, so I will continue doing this stuff. I do that in [northern California’s] East Bay and other places, and I could perhaps do it on a larger scale. I think it's really essential to humanize us all – and science too. I think it leads people to think broadly and openly and to interact with each other.
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