Local anesthetic actions of the TRPA1 agonist cinnamaldehyde

The cation channel TRPA1 has key roles in the detection of noxious chemicals and in the mechanisms underlying pain and neurogenic inflammation. Most of TRPA1 properties have been established through the use of the putative specific agonists cinnamaldehyde (CA) and allyl isothiocyanate (AITC), two chemical irritants present in cinnamon and mustard, respectively. However, we show here that in contrast to AITC, CA elicits very weak irritation in humans and mice, reduces pain responses elicited by other chemical irritants and inhibits sensory nerve responses to thermal and electrical stimulation. We found that, surprisingly, CA blocks neuronal voltage-gated Na+ channels, by interacting with the binding site for local anesthetics. This local anesthetic action of CA explains the distinct sensory properties of CA- and AITC-containing spices and should be considered when using CA to study TRPA1 pathophysiology. Our findings underscore the need exploring the properties of TRP channel modulators beyond this family of chemosensors.