While cannabinoids are known as potent inhibitors of airway inflammation their effect on airway responsiveness is still under debate.

Therefore we performed isometric force measurements of murine trachea in a wire-myograph and found that the endocannabinoid anandamide (AEA) induced a strong dose-dependent airway relaxation. This response was not restricted to large trachea as it was also observed in small intrapulmonary airways of lung slices. Airway relaxation by AEA was independent from CB1/2 receptors because it was unaltered in Cnr1/2 -/- mice; in contrast, a diminished relaxation by AEA was found after pharmacological inhibition of the AEA degradation enzyme fatty acid amide hydrolase (FAAH) with URB-597 and in FAAH-/- mice. In fact, FAAH was strongly expressed on mRNA level in trachea and immunostainings revealed FAAH protein expression in airway epithelial as well as smooth muscle cells. Because FAAH metabolizes AEA to arachidonic acid, an important precursor of eicosanoids, we also examined their contribution to the response. Our experiments show that airway relaxation by AEA appeared to rely on cyclooxygenase (COX) as the COX inhibitor indomethacin attenuated airway relaxation while the cytochrome P450 inhibitor ODYA and the lipoxygenase inhibitor NDGA were without effect. As direct vasorelaxing molecule we identified prostaglandin E2 because antagonists of EP2 and EP4 but not IP receptors could block the response.

Thus, AEA is a strong airway relaxant via its FAAH-dependent metabolization to prostaglandins. In combination with the well-known anti-inflammatory action of endocannabinoids this mechanism could be helpful to develop novel therapeutic approaches against airway obstruction.