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Background  Several observations have suggested that anandamide, an endogenous cannabinoid ligand, plays an important role in the modulation of cough sensitivity. However, it is unknown whether the anandamide membrane transporter plays a role in this modulation. To test this hypothesis, we investigated the effects of VDM11, an anandamide membrane transporter inhibitor, on capsaicin- and anandamide-induced cough.    Methods  The effect of VDM11, an anandamide membrane transporter inhibitor, on capsaicin- and anandamide-induced cough in mice was examined.    Results  VDM11, at doses of 3–10 mg/kg subcutaneously, produced a dose-dependent antitussive effect. This antitussive effect was antagonized by pretreatment with either intraperitoneal administration (3 mg/kg) or inhalation (1 mg/ml) of SR141716A, a cannabinoid receptor (CB1) antagonist. However, intracerebroventricular injection of SR141716A (0.03 mg/mouse) did not alter the effect of VDM11. Exposure of mice to a nebulized solution of 10% DMSO, a vehicle of anandamide, induced a cough response (7.7 ± 0.6 coughs/3 min; n = 10). Exposure of mice to a nebulized solution of anandamide, at concentrations of 0.03, 0.3 and 3 mg/ml, also produced a cough response in a concentration-dependent manner. The number of coughs induced by low dose (0.03 mg/ml) anandamide was significantly less than that of 10% DMSO. On the other hand, the number of coughs induced by high dose (3 mg/ml) anandamide was significantly greater than that of 10% DMSO. When AM251 (1.8 mM), a selective CB1 receptor antagonist, was given by aerosol for 4 min before inhalation of 0.03 mg/ml of anandamide, the number of coughs was significantly increased to the level observed with 10% DMSO alone. When capsazepine (0.3 mM), a selective TRPV1 receptor antagonist, was given via aerosol for 4 min before inhalation of 3 mg/ml of anandamide, the number of coughs was significantly decreased to the levels observed with 10% DMSO alone. The number of coughs induced by high dose (3 mg/ml) anandamide was significantly and dose-dependently reduced by the pretreatment with VDM11.    Conclusion  These results suggest that anandamide, an endogenous cannabinoid ligand, may modulate cough sensitivity and that anandamide transporters play an important role in this modulation. Furthermore, these findings indicate that inhibition of the uptake of anandamide produced a potent antitussive effect and suggests that the anandamide transporter may be a potential target for peripherally acting antitussive drugs.

Effect of N-arachidonoyl-(2-methyl-4-hydroxyphenyl) amine (VDM11), an anandamide transporter inhibitor, on capsaicin-induced cough in mice