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.

1 There is considerable interest in novel therapies for cough, since currently used agents such as codeine have limited beneficial value due to the associated side effects. Sensory nerves in the airways mediate the cough reflex via activation of C-fibres and RARs. Evidence suggests that cannabinoids may inhibit sensory nerve-mediated responses. 2 We have investigated the inhibitory actions of cannabinoids on sensory nerve depolarisation mediated by capsaicin, hypertonic saline and PGE 2 on isolated guinea-pig and human vagus nerve preparations, and the cough reflex in conscious guinea-pigs. 3 The non-selective cannabinoid (CB) receptor agonist, CP 55940, and the selective CB 2 agonist, JWH 133 inhibited sensory nerve depolarisations of the guinea-pig vagus nerve induced by hypertonic saline, capsaicin and PGE 2 . These responses were abolished by the CB 2 receptor antagonist SR144528, and unaffected by the CB 1 antagonist SR141716A. Similarly, JWH 133 inhibited capsaicin-evoked nerve depolarisations in the human vagus nerve, and was prevented by SR144528. 4 Using a guinea-pig in vivo model of cough, JWH 133 (10 mg kg À1 , i.p., 20 min) significantly reduced citric acid-induced cough in conscious guinea pigs compared to those treated with the vehicle control. 5 These data show that activation of the CB 2 receptor subtype inhibits sensory nerve activation of guinea-pig and human vagus nerve, and the cough reflex in guinea-pigs, suggesting that the development of CB 2 agonists, devoid of CB 1 -mediated central effects, will provide a new and safe antitussive treatment for chronic cough.

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Background and purpose: Sensory nerves regulate central and local reflexes such as airway plasma protein leakage, bronchoconstriction and cough. Sensory nerve activity may be enhanced during inflammation such that these protective effects become exacerbated and deleterious. Cannabinoids are known to inhibit airway sensory nerve function. However, there is still controversy surrounding which receptor is involved in eliciting these effects. Experimental approach: We have adopted a pharmacological approach, including using a novel, more selective CB 2 receptor agonist, GW 833972A (1000-fold selective CB 2 /CB 1 ), and receptor selective antagonists to investigate the inhibitory activity of cannabinoids on sensory nerve activity in vitro and in vivo in guinea-pig models of cough and plasma extravasation. Key results: Depolarization of human and guinea-pig isolated vagus nerves in vitro induced by capsaicin was inhibited by GW 833972A. This compound also inhibited the depolarization of guinea-pig vagus by hypertonic saline or prostaglandin (PG)E 2 . In vivo, GW 833972A inhibited citric acid-induced cough in guinea-pigs but not plasma extravasation, and this effect was blocked by a CB 2 receptor antagonist. Conclusions and implications: This confirms and extends previous studies highlighting the role of CB 2 receptors in the modulation of sensory nerve activity elicited both by the exogenous ligands capsaicin and hypertonic saline but also by endogenous modulators such as PGE 2 and low pH stimuli. These data establish the CB 2 receptor as an interesting target for the treatment of chronic cough.