METHODS:
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: