RT Journal Article
SR Electronic
T1 Targeting fatty acid amide hydrolase as a therapeutic strategy for antitussive therapy
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1700782
DO 10.1183/13993003.00782-2017
VO 50
IS 3
A1 Michael A. Wortley
A1 John J. Adcock
A1 Eric D. Dubuis
A1 Sarah A. Maher
A1 Sara J. Bonvini
A1 Isabelle Delescluse
A1 Ross Kinloch
A1 Gordon McMurray
A1 Christelle Perros-Huguet
A1 Marianthi Papakosta
A1 Mark A. Birrell
A1 Maria G. Belvisi
YR 2017
UL http://erj.ersjournals.com/content/50/3/1700782.abstract
AB Cough is the most common reason to visit a primary care physician, yet it remains an unmet medical need. 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 via elevation of endocannabinoids.Primary vagal ganglia neurons, tissue bioassay, in vivo 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.FAAH inhibition produced antitussive activity in guinea pigs with concomitant plasma elevation of the fatty acid amides N-arachidonoylethanolamide (anandamide), palmitoylethanolamide, N-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 via a cannabinoid CB2/Gi/o-coupled pathway and activation of protein phosphatase 2A, resulting in increased calcium sensitivity of calcium-activated potassium channels.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.Fatty acid amide hydrolase inhibition as a target for the development of novel, safe antitussive therapy http://ow.ly/l4ZE30dbbB1