The Effect of Phytocannabinoids on Airway Hyper-Responsiveness, Airway Inflammation, and Cough

Cannabis has been demonstrated to have bronchodilator, anti-inflammatory, and antitussive activity in the airways, but information on the active cannabinoids, their receptors, and the mechanisms for these effects is limited. We compared the effects of Δ 9 -tetrahydrocannabinol, cannabidiol, cannabigerol, cannabichromene, cannabidiolic acid, and tetrahydrocannabivarin on contractions of the guinea pig–isolated trachea and bronchoconstriction induced by nerve stimulation or methacholine in anesthetized guinea pigs following exposure to saline or the proinflammatory cytokine, tumor necrosis factor α (TNF- α ). CP55940 (2-[(1 R ,2 R ,5 R )-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), a synthetic cannabinoid agonist, was also investigated in vitro. The cannabinoids were also evaluated on TNF- α – and lipopolysaccharide-induced leukocyte infiltration into the lungs and citric acid–induced cough responses in guinea pigs. TNF- α , but not saline, augmented tracheal contractility and bronchoconstriction induced by nerve stimulation, but not methacholine. Δ 9 -Tetrahydrocannabinol and CP55940 reduced TNF- α −enhanced nerve-evoked contractions in vitro to the magnitude of saline-incubated trachea. This effect was antagonized by the cannabinoid 1 (CB 1 ) and CB 2 receptor antagonists AM251 [ N -(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H -pyrazole-3-caroxamide] and JTE907 [ N -(1,3-benzodioxol-5-ylmethyl)-1,2-dihydro-7-methoxy-2-oxo-8-(pentyloxy)-3-quinolinecarboxamide], respectively. Tetrahydrocannabivarin partially inhibited the TNF- α −enhanced nerve-evoked contractions, whereas the other cannabinoids were without effect. The effect of cannabidiol and Δ 9 -tetrahydrocannabinol together did not differ from that of the latter alone. Only Δ 9 -tetrahydrocannabinol inhibited TNF- α −enhanced vagal-induced bronchoconstriction, neutrophil recruitment to the airways, and citric acid−induced cough responses. TNF- α potentiated contractions of airway smooth muscle in response to nerve stimulation by enhancing postganglionic acetylcholine release. Δ 9 -Tetrahydrocannabinol and CP55940 inhibited the TNF- α −enhanced acetylcholine release, and hence contraction and bronchoconstriction, through activation of presynaptic CB 1 and CB 2 receptors. The other cannabinoids did not influence cholinergic transmission, and only Δ 9 -THC demonstrated effects on airway hyper-responsiveness, anti-inflammatory activity, and antitussive activity in the airways.