Summary: TRPM8 protein is a sensor responsible for chemical and cold sensations. Acting on this sensor, for example with menthol, is known to change how pain feels. In the new study, researchers found a way to tune this protein so it eases pain without changing the feeling of cold. This finding may help create drugs that work for chronic pain.
Chronic pain is growing around the world. There are many painkillers, but they all fall into a few groups, like opioids and non-steroidal anti-inflammatory drugs (NSAIDs).
NSAIDs work well for moderate short-term pain. But they do not help much with severe pain or chronic pain. Using them for a long time is also linked to many side effects.
Opioids work for both short-term and chronic pain. But they also fail in many chronic pain conditions. And they cause addiction and carry the risk of overdose.
So there is a real need for better, safer drugs for chronic pain, for patients and for chronic pain specialists in St. Louis alike. One new approach is drugs that act on TRPM8 (transient receptor potential melastatin 8) receptors. These receptors sense chemicals, and they also help us feel cold. They react to menthol, which makes things feel cold. They also sense drops in temperature.
We also know that substances acting on these receptors help reduce pain. That is why menthol is often added to creams and balms. But researchers want to make pills that tune these sensors to help manage pain.
The new study came from Arizona State University’s School of Molecular Sciences and Biodesign Center for Personalized Diagnostics. It was published in Science Advances. The researchers found that these receptors started out as chemical sensors. Later, they evolved and began to sense cold.
Why does this matter? When we try to control pain through TRPM8 sensors, we want to reduce pain without upsetting the body’s ability to sense cold or temperature.
Researchers have tested these sensors for a long time. Their problem has been this. Drugs that ease pain through TRPM8 sensors also upset the body’s ability to sense cold. That side effect is not wanted.
Researchers know that the cold feeling from menthol and the cold feeling from ice are two different things. So they want to learn which part of TRPM8 senses chemicals and which part senses cold. Then they can target only the chemical-sensing part and help people with chronic pain.
Early studies also suggest that a faulty TRPM8 protein plays a big role in chronic pain. That is why people with chronic pain may even feel pain when they touch a metal desk.
There are a few ways to learn the shape of this protein. Researchers have studied it in other mammals and animals with backbones. They have used computer methods to see how it changed over evolution. In this new study, they made a few interesting finds.
The study found the part of the protein that senses chemicals and the part that senses cold. And it found a surprise. The chemical-sensing part of TRPM8 seems to have appeared long before the cold-sensing part.
Knowing how sensors like TRPM8 evolved can help us make better, safer painkillers. These finds will help target only the chemical-sensing part of the receptor without upsetting the sense of temperature.
Some drugs that target these receptors are already in late testing. So it is quite likely that safer, better drugs for chronic pain will appear in the near future.
Frequently Asked Questions
What is TRPM8?
TRPM8 (transient receptor potential melastatin 8) is a protein sensor with two jobs. It reacts to chemicals like menthol. And it senses drops in temperature. The Science Advances study found these two jobs sit in different parts of the protein. The chemical-sensing part appeared long before the cold-sensing part did.
Why does menthol help with pain?
Menthol acts on TRPM8, the same receptor that senses cold. That is why it feels cool on the skin. Substances that act on this receptor also turn down pain. That is why menthol is in so many pain creams and balms. The goal now is a pill that works on the same receptor to manage pain from the inside.
Why does touching something cold hurt when you have chronic pain?
Early studies suggest that TRPM8 stops working properly in chronic pain. When this cold and chemical sensor is out of balance, ordinary touch can feel like pain. That is why some people with chronic pain feel pain just from touching a metal desk.
Are there new pain drugs that target TRPM8?
Some drugs that target these receptors are already in late testing. The old problem was that they eased pain but also upset the body’s ability to sense cold. Now researchers know which part of TRPM8 senses chemicals and which part senses cold. So they can aim at the pain side alone. That points toward safer, better chronic pain drugs than today’s opioids and NSAIDs.
Source:
Luu, D. D., Ramesh, N., Kazan, I. C., Shah, K. H., Lahiri, G., Mana, M. D., Ozkan, S. B., & Van Horn, W. D. (2024). Evidence that the cold- and menthol-sensing functions of the human TRPM8 channel evolved separately. Science Advances, 10(25), eadm9228. https://doi.org/10.1126/sciadv.adm9228
Dr. Gurpreet Singh Padda, MD, MBA, MHP
