EFFECT OF THE 2 TACHYKININ ANTAGONISTS, SR-48968 AND SR-140333, ON COUGH INDUCED BY CITRIC-ACID IN THE UNANESTHETIZED GUINEA-PIG

It is now well-established that sensory nerves stimulation in the airway induces bronchoconstriction and inflammation, but also protective reflexes, such as coughing. These effects are mediated through the release of tachykinins (substance P and neurokinin A) and we have recently shown that SR 48968, a tachykinin NK2-receptor antagonist, inhibited cough induced by citric acid, In this paper, we have studied the effects of SR 48968 administered by aerosol. We have also investigated the effects of SR 140333, a tachykinin NK1-receptor antagonist, and the combination of both SR 48968 and SR 140333 to determine whether tachykinin NK1 receptors are involved in cough. Finally, we have studied the combined effects of SR 48968 and salbutamol to find out whether the antitussive effect of SR 48968 is a consequence of the inhibition of bronchoconstriction. Unanaesthetized guinea-pigs were placed in a transparent chamber and exposed to an aerosol of citric acid (0.4 M), The number of coughs was counted by visual inspection and by determination of sounds and pressure variations in the chamber. By the aerosol route, SR 48968 was an efficient antitussive and 16 times more potent than codeine. SR 140333 (0.1-1 mg . kg(-1) i.p.) did not exert any antitussive effect but it potentiated the maximal effect induced by SR 48968, Finally, salbutamol, in a dose (0.3 mg . kg(-1)) which inhibits bronchoconstriction, but not cough induced by citric acid, did not modify the antitussive effect of SR 48968. In conclusion, our results demonstrate that NK2-receptor stimulation plays a predominant role in the regulation of cough reflex, at least in the guinea-pig, as shown by the high potency and efficacy of SR 48968, a tachykinin NK2-receptor antagonist. SR 140333, a NK1-receptor antagonist is unable to inhibit cough by itself, but it potentiates SR 48968 in terms of efficiency. Finally, as salbutamol did not modify the effect of SR 48968, it may be suggested that the antitussive effect of SR 48968 is not related to the inhibition of citric acid-induced bronchoconstriction.