Uncovering the Mystery Behind Cold Sensation and Menthol’s Cooling Effect

Sensing our environment is one of the most important skills that define life. Registering temperatures around us is critical to adapting and protecting ourselves from harm, either from scorching heat or freezing cold.

The microscopic cold sensor in our skin was discovered in the early 2000s. However, exactly how it works remained a mystery. Now, for the first time, researchers from Duke University have captured the sensor in action using advanced microscopy technology, finally revealing how distinct temperatures trigger the receptor to alarm our nervous system. Beyond that, by uncovering the receptor’s molecular structure, scientists can now explain why mint prompts a cooling sensation.

Their findings will be presented this week to a larger audience at the 70th Biophysical Society Annual Meeting in San Francisco and may expand options for pain management, migraine treatment, and dry eye treatment.

Read More: Scientists Are No Closer to Finding a Cure For the Common Cold — Here’s Why

How Menthol Activates the Cold Sensor

Identifying the cold-sensing receptor TRPM8 (Transient Receptor Potential Melastatin 8) and other temperature-sensitive receptors was a milestone in physiology, so much so that the scientists involved in their discovery won a Nobel Prize in 2021. But despite TRPM8’s detection, picturing the molecular mechanism behind its opening and closing was challenging.

“Imagine TRPM8 as a microscopic thermometer inside your body,” said Hyuk-Joon Lee, a postdoctoral fellow at Duke University, in a press release. “It’s the primary sensor that tells your brain when it’s cold. We've known for a long time that this happens, but we didn't know how. Now we can see it.”

Our skin, mouths, and eyes contain millions of sensory neurons where TRPM8 sensors are located. Temperatures between 46°F and 82°F trigger the receptor to open, releasing a nerve signal to the brain. But where do menthol and eucalyptus come in?

“Menthol is like a trick,” explained Lee. “It attaches to a specific part of the channel and triggers it to open, just like cold temperature would. So even though menthol isn’t actually freezing anything, your body gets the same signal as if it were touching ice.”

Cold and Menthol Amplify the Response

The research team used cryogenic electron microscopy (Cryo-EM) to capture how TRPM8 opens in response to specific triggers. Cryo-EM enables visualization of molecules at near-atomic resolution in a frozen state. This helps preserve their delicate structures and allows them to be observed in their natural state.

Although they confirmed that cold temperatures and menthol activate the receptor through detailed Cryo-EM analysis, they discovered a different mechanism of action. Cold initiates changes directly in the pore region — the main target of the receptor — while menthol interacts with another part of the receptor that just happens to transmit its effect to the pore region as well.

“When cold is combined with menthol, the response is enhanced synergistically,” said Lee. “We used this combination to capture the channel in its open state — something that hadn't been achieved with cold by itself.”

Besides uncovering the molecular mechanism that triggers receptor activation, the team also found a specific region that prevents desensitization of the sensor during prolonged cold exposure, naming it the “cold spot.”

Cold Receptor May Guide New Pain Treatments

The team’s discovery may help us understand TRPM8 dysfunction better, which is associated with chronic pain, migraines, dry eyes, and even certain cancers. “[The structural changes give] us a foundation for developing new treatments that target this pathway,” added Lee.

It also clarifies how drugs interacting with TRPM8 work on a molecular level, like acoltremon, a recently approved eye drop sold under the brand name “Tryptyr,” that is chemically related to menthol. By activating TRPM8, it triggers the cooling pathway in the eye nerves, leading to increased tear production.

Overall, the finding provides the first molecular explanation of how physical and chemical triggers cause cold sensation, finally answering a decades-old physiological mystery — and proving to every one of us that feeling the coolness isn’t just in our imagination whenever we pop a mint.

This article is not offering medical advice and should be used for informational purposes only.

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Article Sources

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• This article references information published by the Biophysical Society: Scientists Show How Your Body Senses Cold—And Why Menthol Feels Cool