TY - JOUR T1 - The Effect of Phytocannabinoids on Airway Hyper-Responsiveness, Airway Inflammation, and Cough JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 169 LP - 180 DO - 10.1124/jpet.114.221283 VL - 353 IS - 1 AU - Raj Makwana AU - Radhakrishnan Venkatasamy AU - Domenico Spina AU - Clive Page Y1 - 2015/04/01 UR - http://jpet.aspetjournals.org/content/353/1/169.abstract N2 - 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 Δ9-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-[(1R,2R,5R)-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. Δ9-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 (CB1) and CB2 receptor antagonists AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-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 Δ9-tetrahydrocannabinol together did not differ from that of the latter alone. Only Δ9-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. Δ9-Tetrahydrocannabinol and CP55940 inhibited the TNF-α−enhanced acetylcholine release, and hence contraction and bronchoconstriction, through activation of presynaptic CB1 and CB2 receptors. The other cannabinoids did not influence cholinergic transmission, and only Δ9-THC demonstrated effects on airway hyper-responsiveness, anti-inflammatory activity, and antitussive activity in the airways. ER -