The sensory receptor also underlies the response to a variety of environmental irritants, such as acrolein, the researchers report. Acrolein accounts for the toxic and inflammatory actions of tear gas, vehicle exhaust, tobacco smoke, and the byproduct of some chemotherapy drugs widely used in the treatment of cancer, severe arthritis, multiple sclerosis, and lupus.
"We identified TRPA1 (the receptor) not only as a promising target for the development of new pain medications, but also for potential new treatments of smoking-related disease and environmental irritation," said Sven-Eric Jordt, co-author and assistant professor in the Department of Pharmacology at Yale.
The researchers examined whether neurons taken from mice lacking the TRPA1 receptor responded normally to the pungent compounds found in mustard oil and garlic. They found neurons from the TRPA1-deficient mice were completely insensitive to either ingredient. In fact, the animals lacking the sensory gene did not flinch or try to lick when mustard oil was applied to their paws. Their paws also swelled less and became less sensitive to pain in response to the mustard oil exposure.
The team also found that TRPA1 is an important target of bradykinin, one of the body's natural inflammatory agents that stimulates pain-sensing neurons and leads to hypersensitivity to heat or touch.
Mice lacking the TRPA1 channel had a normal ability to sense extreme cold and noxious sound, evidence against the suggestions of earlier studies that the channels might also play important roles in cold sensitivity or hearing, they found.
"Pain therapy is one of the major challenges in modern medicine," said Jordt. "Currently, 20 percent of all Americans suffer from chronic or inflammatory pain, associated with arthritis, back injuries, headaches, migraines, and shingles."
"Although we are beginning to understand more about the causes of pain, the pharmacological repertoire of pain medications is still very limited. Most of the chemical substances from which current pain therapeutics are derived were discovered more than 100 years ago," he said. "Thus, the development of new pain medications is urgently needed to fill the therapeutic gaps and to treat additional forms of pain."
Co-authors include Diana Bautista, Tetsuro Nikai, Pamela Tsuruda, Jeannie Poblete, Allan Basbaum, and David Julius, of the University of California at San Francisco; Ebenezer Yamoah of the University of California at Davis, and Andrew Read of Yale.
Cell 124: 1-14 (March 23, 2006)