"This study represents the first demonstration that a single gene is responsible for most cool temperature sensation," says team leader Ardem Patapoutian, who has joint appointments with the Department of Cell Biology at Scripps Research and the Genomics Institute of the Novartis Research Foundation. "Many previous candidates have been postulated to play a role in our ability to sense cool temperatures, but none have withstood the test of genetics," he says.

TRPM8 was first discovered by Patapoutian's group and proposed as a key gene controlling cold sensation. To test the hypothesis, the group observed the behavior of mice genetically altered to lack the gene in response to cold stimuli.

When placed in compartments with a temperature gradient, or in an enclosure where they could choose between two temperatures, mice without TRPM8 showed essentially no preference in the temperature range of 18 to 31?°C, suggesting their ability to sense this range was completely disabled without the gene. Normal mice, on the other hand, found cold temperature unpleasant, reliably avoiding cold temperatures in favor of warmer areas.

"It's pretty amazing that one gene could impact thermal sensation this much," says Ajay Dhaka, a Scripps Research postdoctoral fellow in the Patapoutian lab and lead author on the Neuron paper. "It really highlights the importance of the peripheral nervous system and how temperature affects our behavior," he says.

The altered mice also showed little response to the application of acetone to their hindpaw, which causes an unpleasant cold sensation, while the acetone caused normal mice to flick their paw and lick them.

TRPM8 codes for an ion channel found at the tips of sensory neurons, which innervate the skin. When opened, ions flowing through TRPM8 lead to the activation of the sensory neuron, which in turn sends a signal to the brain. The Patapoutian team's results support the idea that activation of TRPM8 by temperature triggers cold sensation. "TRPM8 acts as a gate," says Dhaka, "At warm temperature it remains closed, but opens when exposed to cool temperature."

The TRPM8-deficient mice did not lose their ability to feel pain in response to extreme cold, as evidenced by responses similar to wild type mice when exposed to -1?°C cold plates. This suggests that other genes are responsible for this facet of cold sensation.

Though cold can be unpleasant or painful under certain circumstances, it can also deaden pain, as illustrated by icing an injury to relieve pain. To test this side of cold sensation, the researchers injected the mice with small amounts of a pain-causing chemical, formalin, and then exposed the affected paw area to a cold plate.

Cold temperature clearly reduced the acute pain felt by control mice as shown by a reduction in the response to formalin injection when compared to the amount of time control mice spent flicking and licking their paws when placed on a room temperature plate. In contrast, TRPM8-deficient mice did not receive any acute pain relief from the cold plate suggesting that cold activation of TRPM8 can mediate some of the analgesic effects of cold.

Just how the same sensation can be interpreted as unpleasant under certain circumstances and pleasant in others is still not clear, but is a question the group plans to investigate. "It would be really interesting to find out how the brain takes essentially the same signal and, depending on context, interprets it differently," says Dhaka.

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