Bidirectional control of airway responsiveness by endogenous cannabinoids

Smoking marijuana or administration of its main active constituent, Delta ( 9)-tetrahydrocannabinol (Delta (9)-THC), may exert potent dilating effects on human airways(1-4). But the physiological significance of this observati on and its potential therapeutic value are obscured by the fact that some a sthmatic patients respond to these compounds with a paradoxical bronchospas m(3,5). The mechanisms underlying these contrasting responses remain unreso lved. Here we show that the endogenous cannabinoid anandamide exerts dual e ffects on bronchial responsiveness in rodents: it strongly inhibits broncho spasm and cough evoked by the chemical irritant, capsaicin, but causes bron chospasm when the constricting tone exerted by the vagus nerve is removed. Both effects are mediated through peripheral CB1 cannabinoid receptors foun d on axon terminals of airway nerves. Biochemical analyses indicate that an andamide is synthesized in lung tissue on calcium-ion stimulation, suggesti ng that locally generated anandamide participates in the intrinsic control of airway responsiveness. In support of this conclusion, the CB1 antagonist SR141716A enhances capsaicin-evoked bronchospasm and cough. Our results ma y account for the contrasting bronchial actions of cannabis-like drugs in h umans, and provide a framework for the development of more selective cannab inoid-based agents for the treatment of respiratory pathologies.