BioEd Online

Whether the pain comes from holding an ice cube for too long or staying out on a frigid winter day, the source is clear: it's the cold that hurts. Now researchers have found a protein responsible for provoking pain in response to extreme cold in mice.

The protein, called Na_v1.8, was already known to play a role in detecting tissue damage, and was previously associated with inflammation and pain in response to damaged nerves. Now it looks like the same protein gets involved when the temperature plummets.

Physiologist Katharina Zimmermann at the University of Erlangen-Nuremberg, Germany, and her colleagues found that mice lacking the protein became impervious to pain from cold. Normal mice placed on a plate chilled to 0°C will hop about and lift their feet, but mice engineered to lack Na_v1.8 do not, they found. The results are published this week in Nature.¹

The protein works by helping sodium ions to pass through the cell membrane of neurons, a process that is crucial to transmitting signals — including pain signals — along nerve fibres. It works unusually well in the cold; unlike other similar proteins, its activity doesn't decline as the temperature drops. "That goes against what cells are supposed to do in the cold," says Ardem Patapoutian, a cell biologist at Scripps Research Institute in La Jolla, California, who was not affiliated with the study.

Feeling the chill

The work adds to our increasing appreciation of how we sense temperature. A protein that responds to moderately cold temperatures (and the cool feel of menthol) was recently identified (see "Protein senses cold". When the temperature dips enough to get painful, though, Na_v1.8 becomes a key player.

It's likely that Na_v1.8 is involved in signalling other sensory experiences, such as heat or pressure, says neurobiologist David McKemy of the University of Southern California in Los Angeles. But it's still unclear whether the protein directly responds to cold or is instead transmitting a signal from another receptor, Patapoutian adds.

Zimmermann notes that Na_v1.8 is a member of a family of proteins that has been shared in similar form by a wide range of animals over time. The protein could be important, she speculates, for telling cold-blooded animals when it's time to seek out warmer locales.