title: The effect of phytocannabinoids on airway hyper-responsiveness, airway inflammation, and cough.
abstract: 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-[(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. 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-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 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.
authors: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, Waterloo, London, United Kingdom raj.makwana@outlook.com.
authors: Raj
authors: R
authors: Makwana
authors: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, Waterloo, London, United Kingdom.
authors: Radhakrishnan
authors: R
authors: Venkatasamy
authors: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, Waterloo, London, United Kingdom.
authors: Domenico
authors: D
authors: Spina
authors: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, Waterloo, London, United Kingdom.
authors: Clive
authors: C
authors: Page
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D002188:Cannabis; D019343:Citric Acid; D003371:Cough / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D003511:Cyclohexanols / Q000494:pharmacology; D006168:Guinea Pigs; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control; D007537:Isometric Contraction / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D012137:Respiratory System / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D014132:Trachea / Q000187:drug effects / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha
chemical_list: D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D003511:Cyclohexanols; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019343:Citric Acid; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol