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 byproducts of some chemotherapy drugs widely used in the treatment of cancer, severe arthritis, multiple sclerosis, and lupus. The insights therefore suggest potential new avenues for the development of anti-inflammatory and pain medications, according to the researchers.
The research team, led by David Julius at the University of California San Francisco, report cellular and behavioral evidence in mice linking the sensory ion channel TRPA1 to the pain response evoked by mustard oil, garlic, and acrolein. Mice deficient for TRPA1 also show pronounced deficits in their reaction to a natural agent produced in response to injury, inflammation, or oxygen shortage, they found.
"By understanding what triggers TRP channel receptors, we can learn something new about how pain is sensed," Julius said. The TRP family of channels includes receptors for a variety of natural plant products that elicit pain and inflammation by stimulating a subset of neurons, collectively known as nociceptors.
Earlier studies identified a heat-activated TRP channel as the receptor for capsaicin, the pungent ingredient in chili peppers. Similarly, a cold-activated channel underlies the response to menthol and other cooling agents, previous research showed.
While earlier evidence had shown mustard oil and garlic extract to stimulate TRPA1, it had not been determined whether the channel was their exclusive target, Julius said.
In the current study, the researchers examined whether neurons taken from mice lacking the TRPA1 receptor responded normally to the pungent compounds found in mustard oil and garlic. Neurons from the TRPA1-deficient mice were completely insensitive to either ingredient, they reported.
Furthermore, animals lacking the sensory gene did not flinch or try to lick when mustard oil was applied to their paws, as normal animals do. Their paws also swelled less and became less sensitive to pain in response to mustard oil exposure.
Chemical similarities between the wasabi and garlic ingredients and acrolein led the team to examine that environmental pollutant's ability to stimulate TRPA1 receptors. Cells made to express TRPA1 became responsive to acrolein and a structurally related irritant, they reported.
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.
"By characterizing cellular and behavioral deficits in mice lacking functional TRPA1 channels, we have now demonstrated that the TRPA1 channel constitutes the sole site of mustard oil and garlic action on the nerve cells that elicit tissue damage, discomfort and pain. We've also found that the receptor plays an important role in the response to environmental irritants found in air pollution, smoke, and as a byproduct of some chemotherapy drugs."
Such byproducts of chemotherapeutics are responsible for some medical complications, including side effects of ovarian cancer treatment that can force patients to discontinue therapy, he said.
"Metabolism of such drugs in the liver leads to the production and accumulation of acrolein in urine, which can lead to severe bleeding that usually results in termination of therapy," the researchers wrote.
"We can now begin to consider the idea that, by blocking TRPA1 action, it might be possible to prolong cancer therapy in such cases," Julius said.
The identification of TRPA1 as a specific site of acrolein toxicity also provides a drug target for treating pulmonary and respiratory irritation caused by related chemicals–"a problem that is especially relevant to individuals who suffer from chronic cough or asthma," the researchers said.
Diana M. Bautista, Tetsuro Nikai, Pamela R. Tsuruda, Jeannie Poblete, Allan I. Basbaum, and David Julius of the University of California, San Francisco in San Francisco, CA; Sven-Eric Jordt and Andrew J. Read of Yale University School of Medicine in New Haven, CT; Ebenezer N. Yamoah of the University of California, Davis in Davis, CA. This work was supported by grants from NINDS (D.J.), NIDCR (D.J. and A.I.B.), and NIDCD (E.N.Y.) and a NIH postdoctoral fellowship and Burroughs Welcome Fund Career Award in Biomedical Science (D.M.B.).
Bautista et al.: "TRPA1 Mediates the Inflammatory Actions of Environmental Irritants and Proalgesic Agents." Publishing in Cell 124, 1269–1282, March 24, 2006. DOI 10.1016/j.cell.2006.02.023 www.cell.com