Inhibition of guinea‐pig and human sensory nerve activity and the cough reflex in guinea‐pigs by cannabinoid (CB₂) receptor activation

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. 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. 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. Using a guinea‐pig in vivo model of cough, JWH 133 (10 mg kg −1 , i.p., 20 min) significantly reduced citric acid‐induced cough in conscious guinea pigs compared to those treated with the vehicle control. 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. British Journal of Pharmacology (2003) 140 , 261–268. doi: 10.1038/sj.bjp.0705435