Clinical study finds new drug target for toothache treatment

March 27, 2021 11:21 PM STI

Washington [US], March 27 (ANI): For people with tooth decay, drinking a cold drink can be agony, but now a clinical study by researchers at the Howard Hughes Medical Institute has found that an ion channel called TRPC5 works as a molecular cold sensor in teeth and could serve as a new drug target for the treatment of toothache.
“It’s a unique type of pain,” says David Clapham, vice president and scientific director of the Howard Hughes Medical Institute (HHMI). “It’s just excruciating.”
Now he and an international team of scientists have figured out how teeth feel cold and have identified the molecular and cellular players involved. In mice and humans, dental cells called odontoblasts contain cold-sensitive proteins that detect temperature drops, the team reports on March 26, 2021 in the journal Science Advances. The signals from these cells can ultimately trigger a painful jolt in the brain.
The book explains how an age-old home remedy relieves toothache. The main ingredient in clove oil, used for centuries in dentistry, contains a chemical that blocks the “cold sensor” protein, explains electrophysiologist Katharina Zimmermann, who led the work at Friedrich University. Alexander of Erlangen-Nurnberg in Germany.
The development of drugs that target this sensor even more specifically could potentially eliminate tooth sensitivity to the cold, Zimmermann says. “Once you have a molecule to target, there is a possibility of treatment.”
Teeth break down when films of bacteria and acid eat away at the enamel, the hard, whitish coating of the teeth. As the enamel erodes, pits called cavities form. About 2.4 billion people – about a third of the world’s population – have untreated decay in permanent teeth, which can cause severe pain, including extreme sensitivity to cold.
No one really knew how teeth feel cold, although scientists have come up with one main theory. Tiny canals inside the teeth contain fluid that moves when the temperature changes. Either way, nerves can sense the direction of this movement, which indicates whether a tooth is hot or cold, some researchers have suggested.
“We can’t rule out this theory,” but there was no direct evidence for it, says Clapham, a neurobiologist at HHMI’s Janelia Research Campus. The movement of fluids in teeth – and dental biology in general – is difficult to study. Scientists need to cut through enamel – the hardest substance in the human body – and another tough layer called dentin, all without pulverizing the soft tooth pulp, blood vessels and nerves it contains. Sometimes the entire tooth “falls apart,” Zimmermann says.

Zimmerman, Clapham and their colleagues did not set out to study teeth. Their work has mainly focused on ion channels, the pores of cell membranes that act as molecular gates. After sensing a signal – a chemical message or a change in temperature, for example – the channels close or open wide and allow ions to flood the cell. This creates an electrical impulse which passes from cell to cell. It’s a fast and crucial way to send information to the brain, heart, and other tissues.
About fifteen years ago, when Zimmermann was a postdoctoral fellow in Clapham’s lab, the team discovered that an ion channel called TRPC5 was very sensitive to cold. But the team didn’t know where in the body TRPC5’s cold-sensing ability came into play. It wasn’t the skin, they found. Mice lacking an ion channel could still feel the cold, the team reported in 2011 in the journal Proceedings of the National Academy of Sciences.
After that, “we hit a dead end,” Zimmermann says. The team was sitting at lunch one day discussing the issue when the idea finally hit. “David said, ‘Well, what other tissues in the body feel cold?’ Zimmermann remembers, the answer was teeth.
TRPC5 resides in teeth – and even more so in decayed teeth, study co-author Jochen Lennerz, a pathologist at Massachusetts General Hospital, found after examining samples from adult humans.
A new experimental setup in mice convinced researchers that TRPC5 indeed works as a cold sensor. Instead of opening a tooth and examining only its cells in a dish, Zimmermann’s team looked at the entire system: the jawbone, teeth, and dental nerves. The team recorded neuronal activity when an ice-cold solution touched the tooth.
In normal mice, this icy immersion triggered nervous activity, indicating that the tooth smelled of cold. This is not the case in mice lacking TRPC5 or in teeth treated with an ion channel blocking chemical. It was a key clue that the ion channel could detect cold, Zimmermann says. Another ion channel studied by the team, TRPA1, also appears to play a role.
The team traced the location of TRPC5 to a specific cell type, the odontoblast, which resides between the pulp and dentin. When someone with a tooth exposed to dentin bites on a popsicle, for example, those TRPC5-filled cells pick up the sensation of cold and an “ow!” signal speeds to the brain.
This sharp sensation has not been as widely studied as other areas of science, Clapham says. Tooth pain may not be considered a hot topic, he says, “but it is important and it affects a lot of people.”
Zimmermann points out that the team’s journey to this discovery spanned more than a decade. Understanding the function of particular molecules and cells is difficult, she says. “And good research can take a long time.” (ANI)