David Julius knows pain. The professor of physiology at the University of California, San Francisco School of Medicine has devoted his research to how the nervous system senses pain and how substances such as capsaicin, a chemical that makes peppers spicy, activate pain receptors. In 2019, he received the $ 3 million Life Science Achievement Award for “Discovery of Molecules, Cells, and the Mechanism of Pain.”
Julius et al. Showed how cell membrane proteins called transient receptor potential channels (or TRP channels) play a role in understanding pain and heat or cold, as well as inflammation and hypersensitivity. Much of his work focuses on the mechanism by which capsaicin exerts its powerful effect on the human nervous system.
His team identified the Caspicin-sensitive receptor, TRPV1, and showed that it is also activated by heat and inflammatory chemicals. He recently demonstrated how scorpion venom targets the Wasabi receptor TRPV1. Drug developers are currently investigating whether these receptors can be targeted for non-opioid analgesics.
In addition to his claims about pain, Julius has discovered a receptor that is responsible for the brain signal serotonin. He is also interested in other sensory receptors, such as infrared sensation in snakes and electro-receptors in snakes and fishfish.
website Scientific American He interviewed Julius about his research on pain, our need for it, and how pain can deviate from its purpose.
How did you first become interested in studying pain?
While doing my postdoctoral work, I became interested in the nervous system. I became interested in understanding how neurotransmitters work in the brain, and what the receptors on these transmitters look like, and using genetics and molecular biology to understand some of these questions. I was fascinated by the idea of medicine and traditional health and how scientists use natural products to understand physiology. I became interested in questions about how hallucinogenic substances work – how people discover things like Pivot and use them in rituals. Of course, chemists had discovered the active ingredients of these substances and how they work on the nervous system. But I was really in charge of this whole approach, in which people study some human behavior and bring it into the realm of chemistry, and then use those chemicals as a guide to understanding how the human nervous system works. All of this eventually led me to wonder how some of these factors cause pain in our environment – substances like capsaicin and wasabi. It was a natural journey for me to understand the nervous system from the interest in using natural products.
The idea of studying capsaicin in a supermarket seems to have crossed your mind. How did such a thing happen?
I was looking for hot pepper sauce on the shelves and I thought to myself, “This is a very important and fun thing. “I have to be serious about it.” My wife – who is also a scientist – looked at me and asked, “What are you doing?” And I said, “I’m really confused. “I have to figure out how to solve this problem.” “So stop wasting time,” he said. It was like anything else: the right time, the right people, and the right technology. And Michael Caterina, my lab colleague at the time, was the one who said, “Yeah, I’m taking on this challenge.” And he made an extraordinary effort. You know that this is the way of science: at the right moment, everything fits.
You and your colleagues discovered that capsaicin activates a receptor called TRPV1. How does this help us feel at home?
This receptor is a protein on the surface of nerve cells. It is most often found on nerve cells associated with pain sensation. This receptor is an ion channel that has the shape of a “donut”, and the central hole is closed until something activates it. The ions (often sodium and calcium ions) then travel from outside the cell. When this happens, an electric current is created in the cell and the process of action potential begins. As a result, an electrical signal is sent from the periphery – for example, your lips that have touched the pepper – to the spinal cord. In the spinal cord, neurons (called sensory neurons and primary pain receptors) then send signals to secondary neurons in the spinal cord. In the same way, through a series of neurons, the signal reaches the brain and the centers through which you feel pain or poison.
The interesting thing about this ion channel is that it is activated by heat, thus playing a role in our ability to feel hot things. So this is actually a kind of information convergence, and a hot pepper mimics thermal stimuli. But it also identifies the factors that our body causes in response to inflammation.
Why do we have the ability to feel pain?
One of the interesting things we know about pain is that when there is an injury — damage to tissue, inflammation, or damage to the nerve fibers themselves — the pain usually goes up. And that seems to be due to increased care: When your ankle twists, you need to know that you did something wrong so you can protect it and let it heal. People who do not have this ability – for example, people with diabetes or leprosy (Hansen’s disease) – do not have feelings in their external organs. If they have a foot injury, they do not feel it and do not know that they need to protect themselves, as a result, their wound becomes infected. So this increases the feeling of pain to protect us and to know that we have to cover that point. Of course, sometimes this goes out of control and we have chronic or permanent pain syndrome.
How can we use capsaicin and other receptors to treat pain?
TRPV1 does not just feel pain; This receptor also senses many of the chemicals that are produced during inflammation. These chemicals sit on these pain-sensing nerve fibers to improve their sensitivity to things like temperature, touch, and other chemicals as part of protective reactions. The TRPV1 channel can detect many different inflammatory agents and thus contribute to the increased sensitivity of nerve fibers to the field of injury. And that’s almost all the reason why scientists are interested in these types of molecules as potential points for analgesics: because these molecules are involved in causing chronic pain when injured. So you can imagine that TRPV1 and other channels are important players in regulating the sensitivity of nerve fibers to injury in conditions such as osteoarthritis, inflammation of the bladder or inflammation of the gastrointestinal tract, which are highly associated with the production of inflammatory mediators. What you want to do is reduce the pain of injury. But you do not want to reduce the acute pain, because then you will not have any warning system. So this is almost exactly what scientists want to achieve. And the idea is that by targeting things like TRPV1 and similar molecules, it may be possible to eliminate the ability of inflammatory agents to sensitize nerve fibers – but at the same time maintain the protective, normal function of the pain pathway.
Could these pathways be an alternative to opioids? And how far is it left to reach such a goal?
This is a good question. I do not work with pharmaceutical companies, so I can not say what the technology of the day. But there have been drugs that have been developed for some of these channels, such as TRPV1, the first channel to be identified. These drugs have scored above-average scores on some models of pain in humans, but have had side effects on target: They reduce the patient’s ability to recognize things that are dangerously hot. So there is a concern that people will harm themselves by drinking hot coffee, for example. And another thing is that the subjects tested reported at least temporary fevers – perhaps because these drugs alter the feeling of warmth. I have never seen a drug that you can buy at the pharmacy. But drug development is a long process, and I hope that some of the molecules we have discovered will eventually be targets for new non-opioid analgesics.
Non-opioid receptors are present throughout the nervous system – the brain, spinal cord, pain and sensory fibers. And so opioids have many other effects on the nervous system that can lead to things like respiratory depression, constipation, and cognitive effects. These drugs also cause resistance or addiction. So the initial goal of our work, and the approach that others take in this area, is to focus on the surrounding nerve fibers, such as the skin and other areas specific to the sensation of pain reactions; With the idea that if we can identify molecules that are specific to those points, the side effects of drugs will be less.
You have studied other sensory abilities in addition to pain, right?
Yes. We are generally interested in sensory systems and understanding their overall function – not just the pain pathway. They give your brain the ability to produce an inner view of the outside world. But the fascinating thing I have found about sensory systems is that different animals see the world in different ways. We studied infrared sensation in rattlesnakes because, like everyone else, we thought they were related to the sensation of heat – and because this was close to our understanding of the mechanisms of pain sensation. Recently, people in my lab were working on the mechanism of electro-receptors (sensing electric fields); A trait found in aquatic animals such as sharks or ospreys. Scientists have studied these animals for many years and found that they use these systems (such as infrared and electro-receptors), and have done aesthetic physiological research on their physiology. What had not been studied much was the understanding of the molecular basis of these systems. And now there are many tools, such as DNA and RNA sequencing, that we can use to make connections between molecules and physiology. This is almost where we enter the field. We have used these molecular tools and are reviewing some very beautiful research to be able to create a molecular framework for these physiological and behavioral systems.