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

Raj Makwana*, Radhakrishnan Venkatasamy, Domenico Spina, Clive Page

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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 Delta(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 alpha (TNF-alpha). 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-alpha-and lipopolysaccharide-induced leukocyte infiltration into the lungs and citric acid-induced cough responses in guinea pigs. TNF-alpha, but not saline, augmented tracheal contractility and bronchoconstriction induced by nerve stimulation, but not methacholine. Delta(9)-Tetrahydrocannabinol and CP55940 reduced TNF-alpha-enhanced nerve-evoked contractions in vitro to the magnitude of saline-incubated trachea. This effect was antagonized by the cannabinoid 1 (CB1) 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-alpha-enhanced nerve-evoked contractions, whereas the other cannabinoids were without effect. The effect of cannabidiol and Delta(9)-tetrahydrocannabinol together did not differ from that of the latter alone. Only Delta(9)-tetrahydrocannabinol inhibited TNF-alpha-enhanced vagal-induced bronchoconstriction, neutrophil recruitment to the airways, and citric acid-induced cough responses. TNF-alpha potentiated contractions of airway smooth muscle in response to nerve stimulation by enhancing postganglionic acetylcholine release. Delta(9)-Tetrahydrocannabinol and CP55940 inhibited the TNF-alpha-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 Delta(9)-THC demonstrated effects on airway hyper-responsiveness, anti-inflammatory activity, and antitussive activity in the airways.

Original languageEnglish
Pages (from-to)169-180
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume353
Issue number1
Early online date5 Feb 2015
DOIs
Publication statusPublished - Apr 2015

Keywords

  • GUINEA-PIG AIRWAYS
  • CANNABINOID RECEPTOR AGONIST
  • CB2 RECEPTOR
  • PHARMACOLOGICAL CHARACTERIZATION
  • IN-VITRO
  • NEUROGENIC INFLAMMATIONS
  • INTERNATIONAL UNION
  • ASTHMATIC SUBJECTS
  • SMOKED MARIHUANA
  • WIN 55212-2

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