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Fatty acid amide hydrolase (FAAH) is an enzyme that breaks down endocannabinoids, and inhibition of FAAH produces analgesic and anti-inflammatory effects. Cannabinoids inhibit vagal sensory nerve activation and the cough reflex, so it was hypothesised that FAAH inhibition would produce antitussive activity<jats:italic>via<\/jats:italic>elevation of endocannabinoids.<\/jats:p><jats:p>Primary vagal ganglia neurons, tissue bioassay,<jats:italic>in vivo<\/jats:italic>electrophysiology and a conscious guinea pig cough model were utilised to investigate a role for fatty acid amides in modulating sensory nerve activation in vagal afferents.<\/jats:p><jats:p>FAAH inhibition produced antitussive activity in guinea pigs with concomitant plasma elevation of the fatty acid amides<jats:italic>N<\/jats:italic>-arachidonoylethanolamide (anandamide), palmitoylethanolamide,<jats:italic>N<\/jats:italic>-oleoylethanolamide and linoleoylethanolamide. Palmitoylethanolamide inhibited tussive stimulus-induced activation of guinea pig airway innervating vagal ganglia neurons, depolarisation of guinea pig and human vagus, and firing of C-fibre afferents. These effects were mediated<jats:italic>via<\/jats:italic>a cannabinoid CB<jats:sub>2<\/jats:sub>\/G<jats:sub>i\/o<\/jats:sub>-coupled pathway and activation of protein phosphatase 2A, resulting in increased calcium sensitivity of calcium-activated potassium channels.<\/jats:p><jats:p>These findings identify FAAH inhibition as a target for the development of novel, antitussive agents without the undesirable side-effects of direct cannabinoid receptor agonists.<\/jats:p>","DOI":"10.1183\/13993003.00782-2017","type":"journal-article","created":{"date-parts":[[2017,9,21]],"date-time":"2017-09-21T00:55:28Z","timestamp":1505955328000},"page":"1700782","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Targeting fatty acid amide hydrolase as a therapeutic strategy for antitussive therapy"],"prefix":"10.1183","volume":"50","author":[{"given":"Michael 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