Anandamide induces cough in conscious guinea-pigs through VR1 receptors

1 Endogenous neuronal lipid mediator anandamide, which can be synthesized in the lung, is a ligand of both cannabinoid (CB) and vanilloid receptors (VR). The tussigenic effect of anandamide has not been studied. The current study was designed to test the direct tussigenic effect of anandamide in conscious guinea-pigs, and its effect on VR1 receptor function in isolated primary guinea-pig nodose ganglia neurons. 2 Anandamide (0.3-3 mg-ml(-1)), when given by aerosol, induced cough in conscious guinea-pigs in a concentration dependent manner. When guinea-pigs were pretreated with capsazepine, a VR1 antagonist, the anandamide-induced cough was significantly inhibited. Pretreatment with CBI (SR 141716A) and CB2 (SR 144528) antagonists had no effect on anandamide-induced cough. These results indicate that anandamide-induced cough is mediated through the activation of VR1 receptors. 3 Anandamide (10-100 muM) increased intracellular Ca2+ concentration estimated by Fluo-4 fluorescence change in isolated guinea-pig nodose ganglia cells. The anandamide-induced Ca2+ response was inhibited by two different VR1 antagonists: capsazepine (1 muM) and iodoresiniferatoxin (I-RTX, 0.1 muM), indicating that anandamide-induced Ca2+ response was through VR1 channel activation. In contrast, the CB1 (SR 141716A, 1 muM) and CB2 (SR 144528, 0.1 muM) receptor antagonists had no effect on Ca2+ response to anandamide. 4 In conclusion, these results provide evidence that anandamide activates native vanilloid receptors in isolated guinea-pig nodose ganglia cells and induces cough through activation of VR1 receptors.