How chemistry can help us understand pain and change treatments

UCSF Nobel prize winner David Julius talks about his research and spicy foods

Ancient philosophers and modern-day medical experts have long understood that pain and suffering are a part of life.

But only recently have humans discovered the actual chemicals in our brains that allow us to feel pain sensations. Perhaps more importantly, scientists believe those chemicals can be identified and controlled to help ease our experiences with pain.

At the forefront of this research is biochemist and molecular biologist David Julius, who has a doctorate and chairs the Department of Physiology and holds the Morris Herzstein Chair in Molecular Biology and Medicine at UCSF. This year, he was awarded the 2021 Nobel Prize in Physiology or Medicine for his discoveries of receptors for temperature and touch.

Using substances from the natural world such as chili peppers, horseradish and even snake venom, Julius’ research on how the body feels heat and cold has carved a new frontier for research into the way we measure and treat pain — a pressing issue nationally and locally in San Francisco as The City grapples with the opioid crisis.

The Examiner sat down with Julius recently to learn more about his research and what San Franciscans can learn about the sensations we feel but know so little about. This conversation has been lightly edited for length and clarity.

How do you approach pain as a researcher?

A big part of our work uses chili peppers and capsaicin. The pepper plant produces chemicals to deter a squirrel or deer. It does that because it’s designed to activate neurofibers that are important for pain sensation.

Pain is a pretty complex process and involves the initial step of having a stimulus and transmitting that to your central nervous system. People study pain at all levels of the nervous system. We always gravitated to the pain mechanisms, so where stimulus detection occurs and where it’s easiest to identify molecules involved in pain sensation.

Studying pain is a little more difficult because behaviors are difficult to measure and quantify. With vision, you can flash images in front of a person or animal and can tell you how they see, with taste you can ask if you prefer to taste A or B, and behaviors tell you about their preferences. In the area of pain sensation, it’s more like aversive tests. Poke a paw or hand, put it on a warm surface and see how long they last. But it’s crude and challenging, and that’s the same with trials for drugs.

That’s why I study things at the periphery — I take cells and try to understand what they do. The higher up you go in the nervous system, the more complex it gets as you get to the more cognitive questions.

What is the discovery you’ve made that surprised you the most?

Identifying these molecules to begin with. When we got the results suggesting we were well on our way, that was an amazing moment.

Another was a few years after that. We used menthol to test cold sensation, and that’s a related molecule to the one that senses heat. When we saw those side by side, it gave us all of the molecular frameworks for understanding how we sense temperature.

Touch and pain are something we take for granted. You touch something hot or cold, most of us don’t think too much about. But molecular systems allow us to experience that differently. This is based on real biology and biophysics, and certain molecules allow us to experience the world the way we do.

Here in San Francisco, overdose deaths are skyrocketing. How might your research filter down to the local level to address some of the challenges we’re seeing here with pain treatment?

Short-term interventions and fixes are very necessary. It really comes down to policies about drug administration and how drugs are prescribed and how they are used. You can’t just give somebody a drug; you need more intense interactions with patients.

But even then it can be difficult. When someone has chronic pain and no obvious sign of an injury, how do you know where it is or what is the primary problem? I think we are still a ways off from that. This comes back to how you diagnose pain and treat it. Physical therapy and counseling are also a big part of this.

There are a lot of people who suffer from pain syndromes. For people who have chronic pain syndrome or interact with people who do, we underestimate the degree to which having chronic pain upends your life. Unless you have a family member or deal with this yourself, a lot of times we underestimate this. But being in this field, I’ve come to appreciate how serious chronic conditions can be.

Are there ways our society thinks about and treats pain now that should be changed?

I’m not a clinician, but we need different pharmacological methods to treat pain. We have opiates, aspirin and Ibuprofen. That’s pretty limited. Opiates are great pain suppressors but, as we all know, they have big problems and they are limited in terms of duration, and none of those drugs are effective for all pain sensations. There are different disorders. Migraines are different from knee pain.

Things that are associated with heat and surface pain, which are involved in the detection of inflammation, might be good targets for pain management. Drugs have been developed against them and some score well, but they have other effects like diminishing your ability to know if something is hot.

That’s another challenge in the pain world. You want drugs that can diminish pain when the system becomes hyperactivated, not just shut down the pain pathway and remove its function. You need to have acute protective pain as a survival mechanism. You need to be aware if you’re in contact with something that could hurt you.

What is your research focused on currently?

My lab is small, but we divide ourselves into two overlapping areas. One is to continue using visualization techniques to understand how these molecules work, and how they change shape to transmit signals to the nervous system. That’s important for understanding how this works and for people who want to design new therapeutics.

We also want to better understand visceral pain, like the bladder or the GI tract. What initiates long-term pain if you have something like irritable bowel syndrome? We’re trying to understand what leads to persistent pain when you have inflammation of the gut.

Pain is not just a discriminative property, but it has a huge emotional cognitive component to it, more so than other systems. So, your state of mind does not affect the colors you see as much as the pain you feel. And it’s a two-way street: If you’re suffering from chronic pain you will get depressed if you don’t find solutions to that. People who experience pain are really focused on getting rid of it, I’m sure that changes your psychological status in many ways and it’s hard to tease those apart. I think we are still far away from understanding that.

You have often used chili peppers and wasabi for heat detection research. I have to ask, are you a fan of spicy foods? Has this research changed your pain tolerance along the way?

I do like spices. A friend sent me a box of all these hot sauces so we put them out in a lab, and others in my lab went straight to the 11, one of the hottest. I hovered at 4-5. I like spicy foods, but I have my limits.

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