Targeting fatty acid amide hydrolase as a therapeutic strategy for antitussive therapy

• Published in: The European respiratory journal Vol. 50; no. 3; p. 1700782
• Main Authors: Wortley, Michael A, Adcock, John J, Dubuis, Eric D, Maher, Sarah A, Bonvini, Sara J, Delescluse, Isabelle, Kinloch, Ross, McMurray, Gordon, Perros-Huguet, Christelle, Papakosta, Marianthi, Birrell, Mark A, Belvisi, Maria G
• Format: Journal Article
• Language: English
• Published: England European Respiratory Society Journals Ltd 01.09.2017
• Subjects: Adult; Aged; Amides; Amidohydrolases - antagonists & inhibitors; Analgesics; Anandamide; Animals; Antitussive Agents - therapeutic use; Aza Compounds - pharmacology; Calcium channels; Cannabinoid CB2 receptors; Cannabinoid Receptor Modulators - pharmacology; Cannabinoids - antagonists & inhibitors; Capsaicin - pharmacology; Cough; Cough - drug therapy; Electrophysiology; Enzyme Inhibitors - therapeutic use; Fatty acids; Fatty-acid amide hydrolase; Female; Guinea Pigs; Humans; Hydrolase; Inflammation; Male; Middle Aged; Oleic acid; Palmitoylethanolamide; Phosphoprotein phosphatase; Potassium channels; Primary care; Protein phosphatase; Receptor, Cannabinoid, CB2 - drug effects; Respiratory tract; Spiro Compounds - pharmacology; Vagus nerve; Vagus Nerve - drug effects
• ISSN: 0903-1936; 1399-3003
• DOI: 10.1183/13993003.00782-2017

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 elevation of endocannabinoids.Primary vagal ganglia neurons, tissue bioassay, 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 -arachidonoylethanolamide (anandamide), palmitoylethanolamide, -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 a cannabinoid CB /G -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.