Cannabinoid CB(2) receptor activation prevents bronchoconstriction and airway oedema in a model of gastro-oesophageal reflux.
Cannabinoids have been shown to inhibit sensory nerve activation in guinea-pigs and humans. Their effects are mediated by specific activation of two types of receptors, named CB(1) and CB(2). The purpose of this study was to investigate the effects of WIN 55,212-2, (R)-(+)-[2,3-dihydro-5methyl-3-[(4-morpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone, a non selective agonist of cannabinoid receptors, and JWH 133, (6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran a selective cannabinoid CB(2) receptor agonist, on the sensory nerve component of intraoesophageal (i.oe.) HCl-induced airway microvascular leakage and bronchoconstriction in guinea-pigs. We also tested the effect of WIN 55,212-2 on substance P-induced plasma extravasation and bronchoconstriction. Airway microvascular leakage and bronchoconstriction induced by i.oe. HCl was inhibited by the cannabinoid CB(1)/CB(2) agonist WIN 55,212-2 (0.3-3 mg/kg i.p.) in a dose-dependent manner (maximal inhibition at the dose of 3 mg kg(-1), P<0.01). The effect of WIN 55,212-2 was inhibited by a cannabinoid CB(2) receptor antagonist SR 144528, [N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1] heptan-2yl]-5-(-4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide], but not by a CB(1) receptor antagonist, SR 141716, [N-(piperidin-1yl)-5-(-4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride]. The cannabinoid CB(2) agonist JWH 133 (0.3-3 mg/kg i.p.) mimicked the inhibitory effect of WIN 55,212-2 on HCl-induced microvascular leakage. Under similar conditions, WIN 55,212-2 (1 mg kg (-1) i.p.) was unable to counteract the airway microvascular leakage and bronchoconstriction induced by substance P. These results suggest that inhibition by WIN 55,212-2 of airway plasma extravasation and bronchoconstriction induced by i.oe. HCl instillation in guinea-pigs is mediated through cannabinoid CB(2) receptor activation.
Cui
Yong-Yao
YY
Université Versailles St-Quentin, UPRES EA220, Pharmacology, Foch Hospital, 11, rue Guillaume Lenoir, 92150 Suresnes, France.
D'Agostino
Bruno
B
Risse
Paul-André
PA
Marrocco
Guiseppina
G
Naline
Emmanuel
E
Zhang
Yong
Y
Chen
Hong-Zhuan
HZ
Finance
Olivier
O
Rinaldi-Carmona
Murielle
M
Rossi
Francesco
F
Advenier
Charles
C
D000402:Airway Obstruction / Q000503:physiopathology / Q000517:prevention & control; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001980:Bronchi / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D001892:Camphanes / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004947:Esophagus / Q000187:drug effects; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005764:Gastroesophageal Reflux / Q000503:physiopathology / Q000517:prevention & control*; D006168:Guinea Pigs; D006851:Hydrochloric Acid / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011654:Pulmonary Edema / Q000503:physiopathology / Q000517:prevention & control*; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000502:physiology; D012129:Respiratory Function Tests / Q000379:methods; D000077285:Rimonabant; D014132:Trachea / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology
D048588:Benzoxazines; D001892:Camphanes; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D006851:Hydrochloric Acid; D000077285:Rimonabant; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC