Scientists Learning How People Feel Cold

Feb. 12, 2002 — -- Most have felt the chill of a winter wind, the dull sting of poking a toe in icy water or the cool taste of a cough drop.

But until recently, scientists haven't really understood how we feel these sensations. By tracing which neurons respond to menthol and how they react, researchers have begun to understand exactly how the body feels cold.

Past work has shown that both heat and cold have counterparts in certain foods. Capsaicin, a hot molecule found in chili peppers, is known to elicit the same response in neurons as actual heat. And menthol, a flavoring agent found in mints, cough drops and some cigarettes, has been found to trigger the same sensation as real cold inside the mouth.

In 1997 David Julius of the University of California in San Francisco led a team in successfully tracking down a receptor or protein on the cell's surface, known as VR1, that reacts to heat and begins a process that sends a "heat" signal to the brain.

By placing the neurons of rats inside a petri dish and exposing them to menthol, he and his UCSF colleagues David McKemy and Werner Neuhausser have now identified the receptor for cold, which they dubbed CMR1.

"We knew that menthol has the same effect as a cooling agent," explained Julius. "So we watched how neurons reacted to the menthol."

Julius explains when certain sensory neurons are exposed to menthol, CMR1 binds to the menthol and opens a microscopic gateway, allowing ions (unbalanced atoms) to flow directly into the cell. Sodium and calcium ions, among others, stream inside and activate an electrochemical signal for "cold" that's sent to the brain.

The team published their study in the journal Nature's advanced online publication.

Another group argues feeling cold involves a much more complicated response.

Felix Viana of the Institute of Neuroscience in San Juan de Alicante, Spain, argues there's not a single cold-sensing receptor, but a network of cold-sensing channels that react together to create the cold sensation.

And rather than opening a gateway into neurons, cold causes some channels in cold-sensitive cells to close, Viana's work suggests. When this happens among a network of cells, the electrochemical "cold" signal is sent to the brain. Viana published his work in Nature Neuroscience.

"It's a lot more complicated than Julius' idea," said Amy MacDermott, a physiologist at Columbia University in New York. "It could be that they've identified two different parts of the whole cold-sensing picture."

Julius agrees that the body's sensitivity to cold is probably more complex than we realize. Studies in heat suggest that sensations, in general, can involve several reactions. When Julius "knocked out" the heat-sensitive VR1 receptor in mice, the animals were less sensitive to spicy foods and heat, but could still sense them to a lesser degree.

"It would be naïve to say the entire sensation of cold is mediated through one mechanism," he said. "I think we've shown this receptor plays a role, but it's not alone."

Why bother learning how the body feels cold — or heat, for that matter?

MacDermott explains it's the first step to finding disease treatments. The body's sensitivity for heat and cold is critical for preventing burns, frostbite or hypothermia, but certain conditions can cause a person to feel the sensations when they're not called for. Painkillers designed to target those mechanisms that trigger hot and cold sensations could ease discomfort.

"By understanding what excites a cold sensitive neuron — especially ones telling the body there's extreme cold — we can find ways of controlling it," she said. "It's good to feel cold when it's cold, but we don't need to feel it otherwise."