Spicy plants and venomous beasts are the sources of natural products that have long been used to study how nerves work. At the most recent annual meeting of the Society for Neuroscience (SfN), held November 12-16, 2016, in San Diego, US, David Julius, a physiologist at the University of California, San Francisco, US, delivered a featured lecture summarizing findings from over twenty years of research using compounds found in nature to understand pain.
To this day, plant products used for centuries to quell pain still make up the bulk of our pain medications: powerful pain-relieving opioid drugs derived from the opium poppy; aspirin from the willow tree with its anti-inflammatory effects; and chemical compounds called cannabinoids from Cannabis sativa, the marijuana plant.
“It’s really quite amazing that many of the drugs we rely on today emerged from folk medicine,” Julius said.
SfN is the world’s largest neuroscience conference for scientists and physicians seeking to understand the brain and nervous system.
Hunting the body’s temperature sensors
Julius has worked for years with a chemical called capsaicin, the pungent ingredient in chili peppers. He was the first to isolate using genetic techniques a protein called transient receptor potential vanilloid type 1 (TRPV1). This protein allows pain-sensing nerve cells to send electrical signals in response to capsaicin and heat. Studies by Julius and others on TRPV1 have helped shape researchers’ current understanding of the nerves that transmit painful signals from the body to the spinal cord and ultimately up to the brain.
For his research, rather than look for pain-relieving substances, Julius said he wanted to “flip the coin, and find compounds that would activate pain.” From a long list of compounds, a few emerged that could selectively activate pain-sensing nerve fibers, including capsaicin, menthol—which is cooling but can be painful—and isothiocyanates, volatile substances found in onions and other plants.
TRPV1 and its many cousins in the TRP family of proteins all form ion channels, or pores, in a nerve cell’s outer layer that allow the flow of electrically charged molecules called ions. This gives nerve cells their capacity for electrical signaling.
TRP channels are diverse in function, but many are emerging as important for bodily sensation. Some, including TRPV1, TRPM8 and TRPA1, are activated by plant ingredients but also by intrinsic bodily factors such as temperature and inflammatory signals.
The TRPV1 pore opens in response to capsaicin and temperatures above 45 degrees Celsius —the point at which heat feels painful to humans—whereas TRPM8 is activated by menthol and by temperatures below 26 degrees.
At its core, TRPV1 is a heat sensor; work by Julius and others has shown that TRPV1 has an intrinsic ability to detect heat, regardless of whether other signaling molecules that the channel may respond to are present.
Learning about TRPV1 using mice, and people
In work aimed at discovering the role of TRPV1 and TRPM8, researchers have genetically modified mice so that the animals did not possess the channels. Without TRPV1, mice had difficulty detecting heat. Meanwhile, mice lacking TRPM8 could not distinguish between warm and cool floor plates, identifying the two proteins as key temperature sensors.
But rather than simply functioning only as the body’s heat detector, TRPV1 is now recognized as a protein that can integrate multiple types of signals. This includes inflammatory signals found at sensory nerve endings after injury, which heighten pain sensations.
Previously, researchers developed drugs that inhibit TRPV1 in hopes of relieving pain, but clinical trials revealed significant side effects: the drugs elevated body temperature and made patients less able to sense potentially damaging heat.
Future attempts to dampen pain by inhibiting TRPV1, Julius said, should be directed not at blocking the channel’s heat-sensing ability, but instead at stopping inflammatory molecules from making the channels even more sensitive to painful signals.
Getting inside TRPV1
Recently, Julius and colleagues have focused on studying how the TRPV1 channel opens and moves, and on trying to learn how to safely diminish TRPV1 activity—and pain.
Normally, researchers learn about ion channels by “crystallizing” them—freezing normally dynamic proteins into a solid state so they can be seen with a very powerful microscope. But TRPV1 proved to be a particularly tricky channel, and it resisted crystallization.
In 2013, Julius and collaborators were instead able to visualize the structure of TRPV1 using another technique called electron cryo-microscopy, or cryo-EM. The technique allowed a glimpse of the channels with exquisitely high resolution.
Again turning to substances from the natural world, Julius used resiniferatoxin, a plant compound capable of strongly activating TRPV1, along with a potent toxin from spiders that locks TRPV1 into an open, activated position.
As suspected from previous research, cryo-EM confirmed that TRPV1 contains two separate “gates” within the pore that control the flow of ions—an unusual feature for an ion channel.
Julius is not sure why the channel needs two gates, but, he said, “evolutionarily, it affords the channel rich opportunities for channel modulation—and for drug intervention.” –Stephani Sutherland
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.