Abstract
RATIONALE: Cough is the most frequent reason for consultation with a family doctor, or with a general or respiratory physician. Treatment options are limited and one meta-analysis concluded that over-the-counter remedies are ineffective. There is also increasing concern about their use in children. Environmental irritants such as air pollution and cigarette smoke are thought to evoke cough by stimulating airway sensory nerves; however, how this occurs is not fully understood. OBJECTIVES: We hypothesized that the TRPA1 (transient receptor potential cation channel, subfamily A, member 1) receptor may have a role as a novel target for tussive agents given that many potential irritants have been shown to activate this channel. METHODS: We investigated the effect of TRPA1 ligands on vagal sensory nerve activity in vitro and in guinea pig and human tussive challenge models. MEASUREMENTS AND MAIN RESULTS: We demonstrated that TRPA1 agonists such as acrolein activate cloned human TRPA1 channels in HEK293 cells and also vagal sensory nerves in murine, guinea pig, and human tissues. A role for TRPA1 was confirmed, using specific inhibitors and tissue from Trpa1(-/-) gene-deleted animals. Finally, TRPA1 ligands evoked reproducible tussive responses in both a guinea pig model and normal volunteers. CONCLUSIONS: This study identifies the TRPA1 receptor as a promiscuous receptor, activated by a wide range of stimuli, making it a perfect target for triggering cough and as such one of the most promising targets currently identified for the development of antitussive drugs.