Bidirectional control of airway responsiveness by endogenous cannabinoids

FRANÇAIS :
Chez le rat, l'anandamide, cannabinoïde endogène, exerce deux effets sur les voies aériennes : il inhibe fortement le bronchospasme et la toux produite par des irritants chimiques mais il entraîne un bronchospasme quand l'action du nerf vague est supprimée. Ces deux effets sont conduits à travers les récepteurs cannabinoïques périphériques qui se trouvent sur les axones terminaux des nerfs des voies aériennes.
ENGLISH :
Smoking marijuana or administration of its main active constituent, Delta9-tetrahydrocannabinol (Delta9-THC), may exert potent dilating effects on human airways. But the physiological significance of this observation and its potential therapeutic value are obscured by the fact that some asthmatic patients respond to these compounds with a paradoxical bronchospasm. The mechanisms underlying these contrasting responses remain unresolved. Here we show that the endogenous cannabinoid anandamide exerts dual effects on bronchial responsiveness in rodents: it strongly inhibits bronchospasm and cough evoked by the chemical irritant, capsaicin, but causes bronchospasm when the constricting tone exerted by the vagus nerve is removed. Both effects are mediated through peripheral CB1 cannabinoid recep- tors found on axon terminals of airway nerves. Biochemical analyses indicate that anandamide is synthesized in lung tissue on calcium-ion stimulation, suggesting 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 may account for the contrasting bronchial actions of cannabis-like drugs in human, and provide a framwork for the development of more selective cannabinoid-based agents for the treatment of respiratory pathologies. (Author' s abstract)