Uncovering the Mystery Behind Cold Sensation and Menthol’s Cooling Effect
Perception of our surroundings is one of the most important life-defining skills. Recording the temperatures around us is essential to adapt and protect ourselves from dangers, whether it’s scorching heat or freezing cold.
The microscopic cold sensor present in our skin was discovered in the early 2000s. However, its exact functioning remains a mystery. Now, for the first time, researchers at Duke University have captured the sensor in action using advanced microscopy technology, finally revealing how distinct temperatures trigger the receptor’s alarm on our nervous system. Beyond that, by uncovering the molecular structure of the receptor, scientists can now explain why mint causes a cooling sensation.
Their findings will be presented to a wider audience this week at the 70th annual meeting of the Biophysical Society in San Francisco and could expand options for pain management, migraine treatment and dry eye treatment.
Learn more: Scientists are no closer to finding a cure for the common cold – here’s why
How menthol activates the cold sensor
The identification of the cold-sensitive 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 the detection of TRPM8, imagining the molecular mechanism behind its opening and closing was a challenge.
“Think of TRPM8 as a microscopic thermometer inside your body,” Hyuk-Joon Lee, a postdoctoral researcher at Duke University, said in a press release. “It’s the main 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, mouth 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 what is the place of menthol and eucalyptus?
“Menthol is like a thing,” Lee explained. “It attaches to a specific part of the channel and triggers it to open, just like a cold temperature would. So even though the menthol doesn’t freeze anything, your body gets the same signal as if it touched 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 allows visualization of molecules at near-atomic resolution in a frozen state. This allows us to preserve their delicate structures and observe them 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 which also transmits its effect to the pore region.
“When cold is combined with menthol, the response is enhanced synergistically,” Lee said. “We used this combination to capture the channel in its open state, which had not been achieved with cold alone.”
In addition to uncovering the molecular mechanism that triggers receptor activation, the team also discovered a specific region that prevents desensitization of the sensor during prolonged exposure to cold, naming it the “cold spot.”
Cold receptor may guide new pain treatments
The team’s discovery could help us better understand TRPM8 dysfunction, which is associated with chronic pain, migraines, dry eye and even certain cancers. “[The structural changes give] “We provide a basis for developing new treatments targeting this pathway,” Lee added.
It also clarifies how drugs that interact with TRPM8 work at the molecular level, such as acoltremon, a recently approved eye drop sold under the brand name “Tryptyr,” which is chemically related to menthol. By activating TRPM8, it triggers the cooling pathway in the eye nerves, leading to increased tear production.
Overall, this discovery provides the first molecular explanation for how physical and chemical triggers cause a feeling of cold, finally answering a decades-old physiological mystery — and proving to all of us that feeling cool isn’t just in our imagination every time we pop a mint.
This article does not offer medical advice and should be used for informational purposes only.
Learn more: Upside-down skull reveals Neanderthal noses lacked special features to cope with cold air
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