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 cannabinod 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 a large conductance Ca²⁺-activated K⁺ channel (Maxi-K⁺ channel) blocker, 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.