Cannabis has been demonstrated to have bronchodilator, anti-inflammatory and anti-tussive activity in the airways, but, information on the active cannabinoids, their receptors and the mechanisms for their 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 anaesthetised guinea-pigs following exposure to saline or the pro-inflammatory cytokine, TNF-α. CP55940, a synthetic cannabinoid agonist was also investigated in vitro. The cannabinoids were also evaluated on TNF−α- and LPS-induced leucocyte 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 antagonised by the CB1 and CB2 receptor antagonist AM251 and JTE907, respectively. Tetrahydrocannabivarin partially inhibited the TNF−α-enhanced nerve-evoked contractions. 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 to nerve stimulation by enhancing postganglionic acetylcholine release. Δ9-THC and CP55940 inhibited the TNF−α-enhanced acetylcholine release, hence contraction and bronchoconstriction, through activation of pre-synaptic CB1 and CB2 receptors. The other cannabinoids did not influence cholinergic transmission and only Δ9-THC demonstrated effects on airway hyperresponsiveness, anti-inflammatory activity and antitussive activity in the airways.
- The American Society for Pharmacology and Experimental Therapeutics