Transient receptor potential ankyrin receptor 1 is a novel target for pro-tussive agents.
OBJECTIVE
The transient receptor potential ankyrin receptor 1 (TRPA1) is a cation channel, co-expressed with the pro-tussive transient receptor potential vanilloid type 1 (TRPV1) channel in primary sensory neurons. TRPA1 is activated by a series of irritant exogenous and endogenous alpha,beta-unsaturated aldehydes which seem to play a role in airway diseases. We investigated whether TRPA1 agonists provoke cough in guinea pigs and whether TRPA1 antagonists inhibit this response.


METHODS
Animals were placed in a Perspex box, and cough sounds were recorded and counted by observers unaware of the treatment used.


RESULTS
Inhalation of two selective TRPA1 agonists, allyl isothiocyanate and cinnamaldehyde, dose-dependently caused cough in control guinea pigs, but not in those with airway sensory nerves desensitized by capsaicin. Coughs elicited by TRPA1 agonists were reduced by non-selective (camphor and gentamicin) and selective (HC-030031) TRPA1 antagonists, whereas they were unaffected by the TRPV1 antagonist, capsazepine. Acrolein and crotonaldehyde, two alpha,beta-unsaturated aldehydes recently identified as TRPA1 stimulants and contained in cigarette smoke, air pollution or produced endogenously by oxidative stress, caused a remarkable tussive effect, a response that was selectively inhibited by HC-030031. Part of the cough response induced by cigarette smoke inhalation was inhibited by HC-030031, suggesting the involvement of TRPA1.


CONCLUSIONS
A novel pro-tussive pathway involves the TRPA1 channel, expressed by capsaicin-sensitive airway sensory nerves and is activated by a series of exogenous (cigarette smoke) and endogenous irritants. These results suggest TRPA1 may be a novel target for anti-tussive medicines.
Centre of Excellence for the Study of Inflammation, University of Ferrara, Italy.
E
E
Andrè
R
R
Gatti
M
M
Trevisani
D
D
Preti
P G
PG
Baraldi
R
R
Patacchini
P
P
Geppetti
D000171:Acrolein / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D003371:Cough / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006168:Guinea Pigs; D017879:Isothiocyanates / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D018384:Oxidative Stress; D012906:Smoke / Q000009:adverse effects; D050051:Transient Receptor Potential Channels / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism
D000996:Antitussive Agents; D017879:Isothiocyanates; D012906:Smoke; D050051:Transient Receptor Potential Channels; D000171:Acrolein; C004471:allyl isothiocyanate; D002211:Capsaicin; C012843:cinnamaldehyde