Cannabinoid receptor agonists inhibit sensory nerve activation in guinea pig airways.
We examined the effects of cannabinoid receptor agonists on various respiratory reactions induced by the activation of capsaicin-sensitive afferent sensory nerves (C-fibers). (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-merpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone (WIN 55212-2) dose-dependently inhibited electrical field stimulation- and capsaicin-induced guinea pig bronchial smooth muscle contraction, but not the neurokinin A-induced contraction. A cannabinoid CB2 receptor antagonist, [N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide] (SR 144528), reduced the inhibitory effect of WIN 55212-2, but not a cannabinoid CB1 antagonist, [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride] (SR 141716A). A cannabinoid CB2 agonist, JWH 133, also inhibited electrical field stimulation-induced guinea pig bronchial smooth muscle contraction and its inhibitory effect was blocked by SR 144528. The inhibitory effect of WIN 55212-2 on electrical field stimulation-induced bronchial contraction was reduced by the pretreatment of large conductance Ca(2+)-activated K+ channel (Maxi-K+ channel) blockers, iberiotoxin and charybdotoxin, but not other K+ channel blockers, dendrotoxin or glibenclamide. A Maxi-K+ channel opener, 1-(2'-hydroxy-5'-trifluoromethylphenyl)-5-trifluoromethyl-2(3H)benzimidazolone (NS1619), inhibited bronchial contraction induced by electrical field stimulation. WIN 55212-2 and JWH 133 blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea pig airway tissues. These findings suggest that WIN 55212-2 inhibit the activation of C-fibers via cannabinoid CB2 receptors and Maxi-K+ channels in guinea pig airways.
Department of Pediatric, Dokkyo University School of Medicine, Tochigi, Japan. shigemi@dokkyomed.ac.jp
Shigemi
S
Yoshihara
Hiroshi
H
Morimoto
Yumi
Y
Yamada
Toshio
T
Abe
Osamu
O
Arisaka
D000704:Analysis of Variance; D000818:Animals; D048588:Benzoxazines; D001892:Camphanes / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists; D004195:Disease Models, Animal; D004558:Electric Stimulation; D006168:Guinea Pigs; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology; D015288:Neurokinin A; D010880:Piperidines / Q000494:pharmacology; D011336:Probability; D011720:Pyrazoles / Q000494:pharmacology; D012132:Respiratory Muscles / Q000187:drug effects* / Q000294:innervation; D000077285:Rimonabant; D012680:Sensitivity and Specificity; D011984:Sensory Receptor Cells / Q000187:drug effects*
D048588:Benzoxazines; D001892:Camphanes; D063387:Cannabinoid Receptor Antagonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; 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; D015288:Neurokinin A; D000077285:Rimonabant