The mysterious molecular culprit of cold toothache

There’s nothing like the quirky, heartbreaking reaction of a damaged tooth exposed to something cold – a bite of ice cream or a cold drink and all of a sudden that sharp, stabbing sensation, like a needle piercing a nerve.

Researchers have known for years that this phenomenon is the result of damage to the tooth’s protective outer layer. But it has been difficult to figure out how the message goes from the outside of your tooth to the internal nerves. On Friday, biologists reported in the journal Science Advances that they have identified an unexpected player in this painful sensation: a protein embedded in the surface of cells within teeth. The discovery provides a glimpse of the connection between the outside world and the inside of a tooth, and could one day help guide the development of treatments for tooth pain.

More than a decade ago, Dr. Katharina Zimmerman, now a professor at Friedrich-Alexander University in Germany, discovered that cells that produce a protein called TRPC5 were sensitive to cold. When things cooled, TRPC5 opened to form a channel, allowing ions to flow through the cell membrane.

Ion channels like TRPC5 are spread throughout our bodies, Dr. Zimmerman said, and are behind some surprisingly familiar sensations. For example, if your eyes begin to feel cold and dry in the cold air, it is the result of the activation of an ion channel in the cornea. He wondered what other parts of the body could use a cold receptor like TRPC5. And it occurred to him that “the most sensitive tissue in the human body may be the teeth” when it comes to sensations of cold.

Within the protective layer of your enamel, your teeth are made of a hard substance called dentin that is intertwined with tiny tunnels. At the heart of dentin is the soft pulp of the tooth, where nerve cells and so-called odontoblasts, which make dentin, intertwine.

The prevailing theory about how teeth feel cold was that changes in temperature put pressure on the fluid in the dentin tunnels, somehow eliciting a response in those hidden nerves. But there were few details about how exactly that could be happening and what could be bridging the gap between them.

Dr. Zimmerman and her colleagues sought to see if mice engineered to lack the TRPC5 channel still felt toothache like normal mice did. They were intrigued to discover that these mice, when they had damage to their teeth, did not behave as if something was wrong. In fact, they looked pretty much the same as if they’d been given an anti-inflammatory pain reliever, Dr. Zimmerman said.

His co-author Dr. Jochen Lennerz, a pathologist at Massachusetts General Hospital, examined human teeth for signs of the ion channel and found it in their nerves and other cells. That suggested that the channel could play a role in a person’s perception of cold.

Over many years, researchers built a way to accurately measure the nerve signals that come out of a mouse’s damaged molar. They tested their ideas with molecules that could block the activity of various channels, including TRPC5.

The picture they slowly gathered is that TRPC5 is active in odontoblasts. That was a bit surprising, since these supporting cells are better known for producing and maintaining dentin, not for assisting in perception. Inside the odontoblasts, Dr. Lennerz said, TRPC5 opens when the cold signal travels down the dentin tunnels, and this results in a message being sent to the nerves.

As it happens, one substance that prevents TRPC5 from opening is eugenol, the main ingredient in clove oil, a traditional toothache treatment. Although the US Food and Drug Administration is ambiguous about the efficacy of eugenol, if it reduces pain in some people, it may be due to its effect on TRPC5.

Perhaps the knowledge that this channel is at the heart of cold-induced pain will lead to better dental pain treatments down the road – better ways to prevent that message from becoming overwhelming.

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