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-incluced 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-yi)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-H-1-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 SIR 144528. The inhibitory effect of WIN 55212-2 on electrical field stimulation-induced bronchial contraction was reduced by the pretreatment of large conductance Ca2+-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 (3 H) 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.