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Cannabinoid Receptor Agonists Inhibit Sensory Nerve Activation in Guinea Pig Airways

Department of Pediatrics, Dokkyo University School of Medicine, Tochigi; and Department of Pharmacology, Medical Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan

Correspondence and requests for reprints should be addressed to Shigemi Yoshihara, M.D., Department of Pediatric, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, Japan. E-mail: shigemi{at}dokkyomed.ac.jp

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 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(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.

Key Words: airway • cannabinoid • C-fibers • guinea pig • Maxi-K⁺ channels

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