Transient receptor potential ankyrin receptor 1 is a novel target for pro‐tussive agents

Abstract

Background and purpose: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 a,b-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. Experimental approach: Animals were placed in a Perspex box, and cough sounds were recorded and counted by observers unaware of the treatment used. Key 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 a,b-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 and implications: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.

Transient Receptor Potential A1 Channels

“…45 Indeed, recent data from our laboratory have shown that the TRPA1-selective agonists acrolein and cinnamaldehyde induce coughing in guinea pigs and human volunteers, respectively. 45 This fi nding has been confi rmed by Andrè and colleagues, 46 who stimulated coughing in guinea pigs with aerosolized TRPA1-selective agonists and subsequently demonstrated inhibition of these responses with both selective and nonselective TRPA1 blockers. In addition, cigarette smoke-induced cough in guinea pigs can also be partially ( ‫ف‬ 50%) inhibited by HC-030031.…”

“…In addition, cigarette smoke-induced cough in guinea pigs can also be partially ( ‫ف‬ 50%) inhibited by HC-030031. 46 It may be that the tussive response remaining may be mediated by activation of neuronal nicotinic acetylcholine receptors, as a role for these receptors has been identifi ed in cigarette smoke-induced cough in normal volunteers. 47 That TRPA1 has been identifi ed as a pro-tussive receptor in both clinical trials and a guinea Figure 2.…”

Selective inhibition of vagal afferent nerve pathways regulating cough using Nav 1.7 shRNA silencing in guinea pig nodose ganglia

“…Jugular C-fibers terminate throughout the extrapulmonary and intrapulmonary airways while nodose Cfibers sparsely innervate the extrapulmonary airways (26). Stimuli that activate both nodose and jugular ganglia C-fibers in guinea pigs readily evoke coughing when delivered as aerosols to conscious guinea pigs (1,4,6,9,12,18). Which of these C-fiber subtypes drive the cough reflex in conscious guinea pigs has not previously been determined.…”

The emerging role of transient receptor potential channels in chronic lung disease

“…TRPA1 antagonists have been demonstrated to inhibit sensory nerve activation and cough evoked by TRPA1 agonists and inflammatory mediators such as PGE 2 and bradykinin following activation of their respective GPCRs and cough in response to citric acid (low pH solution) [23,[61][62][63][64]. Cinnamaldehyde, a TRPA1 agonist, has been shown to cause cough in clinical studies in normal volunteers [63].…”