Endogenous Cannabinoid Receptor Agonists Inhibit Neurogenic Inflammations in Guinea Pig Airways

Abstract

Background: Although neurogenic inflammation via the activation of C fibers in the airway must have an important role in the pathogenesis of asthma, their regulatory mechanism remains uncertain. Objective: The pharmacological profiles of endogenous cannabinoid receptor agonists on the activation of C fibers in airway tissues were investigated and the mechanisms how cannabinoids regulate airway inflammatory reactions were clarified. Methods: The effects of endogenous cannabinoid receptor agonists on electrical field stimulation-induced bronchial smooth muscle contraction, capsaicin-induced bronchoconstriction and capsaicin-induced substance P release in guinea pig airway tissues were investigated. The influences of cannabinoid receptor antagonists and K⁺ channel blockers to the effects of cannabinoid receptor agonists on these respiratory reactions were examined. Results: Both endogenous cannabinoid receptor agonists, anandamide and palmitoylethanolamide, inhibited electrical field stimulation-induced guinea pig bronchial smooth muscle contraction, but not neurokinin A-induced contraction. A cannabinoid CB2 antagonist, SR 144528, reduced the inhibitory effect of endogenous agonists, but not a cannabinoid CB1 antagonist, SR 141716A. Inhibitory effects of agonists were also reduced by the pretreatment of large conductance Ca²⁺-activated K⁺ channel (maxi-K⁺ channel) blockers, iberiotoxin and charybdotoxin, but not by other K⁺ channel blockers, dendrotoxin or glibenclamide. Anandamide and palmitoylethanolamide blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea pig airway tissues. Additionally, intravenous injection of palmitoylethanolamide dose-dependently inhibited capsaicin-induced guinea pig bronchoconstriction, but not neurokinin A-induced reaction. However, anandamide did not reduce capsaicin-induced guinea pig bronchoconstriction. Conclusions: These findings suggest that endogenous cannabinoid receptor agonists inhibit the activation of C fibers via cannabinoid CB2 receptors and maxi-K⁺ channels in guinea pig airways.

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

“…It should be noted, however, that in this study bronchoconstriction was induced by a calcium ionophore rather than capsaicin. In an in vitro study of guinea pig airway smooth muscle (Yoshihara et al, 2005), anandamide and palmitoylethanolamide inhibited contractions elicited by electrical field stimulation but not by neurokinin A, and also blocked capsaicincapsaicin-induced release of substance P-like immunoreactivity. These effects were selectively inhibited by a CB 2 but not a CB 1 antagonist, or by maxi-K ϩ channel blockers, suggesting that CB 2 agonists may have therapeutic value in asthma (Yoshihara et al, 2005).…”

“…In an in vitro study of guinea pig airway smooth muscle (Yoshihara et al, 2005), anandamide and palmitoylethanolamide inhibited contractions elicited by electrical field stimulation but not by neurokinin A, and also blocked capsaicincapsaicin-induced release of substance P-like immunoreactivity. These effects were selectively inhibited by a CB 2 but not a CB 1 antagonist, or by maxi-K ϩ channel blockers, suggesting that CB 2 agonists may have therapeutic value in asthma (Yoshihara et al, 2005). In a recent study, inhibition of anandamide transport potently suppressed capsaicin-induced cough in mice, suggesting that the anandamide transporter may be a target for peripherally acting antitussive medications (Kamei et al, 2006).…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…Pure ⌬ 9 -THC produces bronchodilation in asthmatic patients (329) and may have therapeutic value in asthma also by virtue of its anti-inflammatory effects (933). Indeed, in allergic airway disease induced in mice by aerosolized ovalbumin, pretreatment with ⌬ 9 -THC inhibits the expression of T-cell cytokines elicited by ovalbumin in the lungs and the associated inflammatory response (389).…”

Prejunctional and peripheral effects of the cannabinoid CB1 receptor inverse agonist rimonabant (SR 141716)

“…Thus, inhibition of the electrically induced contraction of the guinea pig trachea is vanilloid-receptor mediated (Nieri et al 2003), whereas the sensory nerve-related activation of the guinea pig and human vagus nerve (Patel et al 2003) or the inhibition of electrically stimulated rat (Yousif and Oriowo 1999) and guinea pig airway contraction (Yoshihara et al 2004(Yoshihara et al , 2005 is CB 2 -receptor mediated. A CB 2 receptor has also been implicated in the inhibition of capsaicin-induced bronchoconstriction in some studies (Patel et al 2003;Yoshihara et al 2004Yoshihara et al , 2005. By contrast, other in vitro studies using electrically induced noradrenaline release (Vizi et al 2001) and in vivo studies using capsaicin-induced bronchoconstriction (Calignano et al 2000) reported an inhibitory effect of cannabinoids in the guinea pig in a rimonabant-sensitive and hence CB 1 -mediated manner.…”

“…Cannabinoids can affect airway function in rats (Yousif and Oriowo 1999), guinea pigs (Calignano et al 2000;Yoshihara et al 2004Yoshihara et al , 2005, and humans (Patel et al 2003). Many of these effects are rimonabant insensitive and rather involve vanilloid or CB 2 receptors.…”