Anti-tussive effects of FAAH inhibition: The role of endocannabinoids and downstream signalling pathways in the inhibition of vagal sensory nerve activation

Abstract

Cough is an essential reflex, but chronic cough can be a problematic symptom of respiratory diseases, for which no effective and safe medications are available. We have shown that inhibition of fatty acid amide hydrolase (FAAH) elevates endocannabinoids (inc. palmitoylethanolamide, anandamide, oleoylethanolamide & linoleoylethanolamide: PEA, AEA, OEA, LEA) and inhibits citric-acid evoked cough in guinea pigs, and PEA inhibits sensory nerve depolarisation1. We investigated the pathway of endocannabinoid inhibition of sensory nerve/neuron activity. PEA, AEA, OEA & LEA inhibited capsaicin-induced depolarisation of isolated guinea pig vagus nerve via the CB2 (but not CB1) receptor, and capsaicin-induced calcium influx in airway-terminating jugular neurons – i.e. cough reflex relevant vagal neurons. Using vagus nerve from PTX dosed guinea pigs we showed PEA inhibition required the Gαi protein. PEA inhibition also required small conductance K+ channel (SKCa) activation, and concurrent with SKCa mediated suppression of nerve activation, PEA inhibited depolarisation by TRPA1 & TRPV4 agonists. Finally, PEA increases the calcium sensitivity of SKCa via protein phosphatase 2A activation. Key experiments paralleled in human vagus nerve indicate this pathway translates to man. In summary, endocannabinoids inhibit sensory nerve activation in guinea pig and human vagus nerve via CB2–Gαi–PP2A–SKCa. This data implies that inhibiting FAAH/elevating endocannabinoids may be beneficial in conditions driven by excessive peripheral sensory nerve activation including chronic cough. 1. Adcock et al. (2011) Proc Br Pharmacol Soc.9: A025p.