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.

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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.

CT measurements of small vessels support a distinct vessel-related phenotype in patients with COPD with severe PH, and combined with WT and PaO2 parameters in the paw score, which may offer a non-invasive tool to select patients for RHC.