Characterization of the effects of cannabinoids on guinea-pig tracheal smooth muscle tone: role in the modulation of acetylcholine release from parasympathetic nerves

1 We investigated the ability of the cannabinoid agonists CP55,940 (CB1/CB2 ) and anandamide (endogenous cannabinoid) to modulate electrical field stim ulation (EFS)-induced acetylcholine (ACh) release from parasympathetic nerv e terminals innervating guinea-pig trachea. We assessed whether modulation of transmitter release translated to an impact on functional responses: by investigating the effect of these agents on contractile responses evoked by EFS and ACh. Furthermore, we evaluated the ability of these compounds to e licit bronchodilation in precontracted guinea-pig tracheal strips. 2 CP55,940 and anandamide significantly inhibited EFS-evoked ACh release (m aximal inhibition of 35.1+/-2.9% and 33.4+/-6.4% at 1 mu M, P<0.05, respect ively). The CB1 receptor antagonist SR 141716A (1 mu M), had no effect on A Ch release and failed to reverse the inhibitory effect of CP55,940 (1 mu M) . 3 Paradoxically, CP55,940 had no significant effect on EFS-evoked cholinerg ic contractile responses. Furthermore, CP55,940 did not relax pre-contracte d tracheal strips or affect contractile responses to exogenous ACh. This la ck of activity on smooth muscle tone is consistent with the fact that no de tectable specific binding of [H-3] CP55,940 was found in tracheal homogenat es. 4 These data suggest that cannabinoid agonists inhibit ACh release from cho linergic nerve terminals via activation of CB2 receptors but that this inhi bitory action does not impact on functional responses such as cholinergic c ontraction.