TRPA1 Antagonists Block the Noxious Effects of Toxic Industrial Isocyanates and Tear Gases

Abstract

The release of the methyl isocyanate in Bhopal, India, caused the worst industrial accident in history. Exposures to industrial isocyanates induce lacrimation, pain, airway irritation and edema. Similar responses are elicited by chemicals used as tear gases. Despite of frequent exposures the biological targets of isocyanates and tear gases in vivo have not been identified, precluding the development of effective countermeasures. We use Ca2+ imaging and electrophysiology to show that the noxious effects of isocyanates and all major tear gas agents are caused by activation of Ca2+ influx and membrane currents in mustard oil‐sensitive sensory neurons. These responses are mediated by Transient Receptor Potential Ankyrin 1 (TRPA1), an ion channel serving as a detector for reactive chemicals. In mice, genetic ablation or pharmacological inhibition of TRPA1 dramatically reduces isocyanate‐ and tear gas‐induced nocifensive behavior following both ocular and cutaneous exposures. We conclude that isocyanates and tear gas agents target the same neuronal receptor, TRPA1. TRPA1 antagonists can prevent and alleviate the adverse health effects of exposures to a wide range of toxic noxious chemicals.