The effect of phytocannabinoids on airway hyper-responsiveness, airway inflammation, and cough

J Pharmacol Exp Ther. 2015 Apr;353(1):169-80. doi: 10.1124/jpet.114.221283. Epub 2015 Feb 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Resistance / drug effects
  • Animals
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoalveolar Lavage Fluid / immunology
  • Bronchoconstriction / drug effects
  • Cannabinoid Receptor Agonists / pharmacology
  • Cannabinoids / pharmacology*
  • Cannabis
  • Citric Acid
  • Cough / chemically induced
  • Cough / immunology
  • Cough / prevention & control*
  • Cyclohexanols / pharmacology
  • Guinea Pigs
  • Inflammation / chemically induced
  • Inflammation / immunology
  • Inflammation / prevention & control
  • Isometric Contraction / drug effects
  • Lipopolysaccharides / pharmacology
  • Male
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiopathology
  • Respiratory Hypersensitivity / immunology
  • Respiratory Hypersensitivity / physiopathology
  • Respiratory Hypersensitivity / prevention & control*
  • Respiratory System / drug effects*
  • Respiratory System / immunology
  • Respiratory System / physiopathology
  • Trachea / drug effects
  • Trachea / physiopathology
  • Tumor Necrosis Factor-alpha


  • Cannabinoid Receptor Agonists
  • Cannabinoids
  • Cyclohexanols
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Citric Acid
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol