Central antitussive activity of the NK1 and NK2 tachykinin receptor antagonists, CP-99,994 and SR 48968, in the guinea-pig and cat

1 The purpose of this study was to investigate the antitussive activity and sites of action of the NK1 and NK2 tachykinin receptor antagonists, CP-99,994, SR 48968, and the racemate of SR 48968, SR 48212A in the cat and guinea-pig. 2 Guinea-pigs were dosed subcutaneously (s.c.) with CP-99,994, SR 48212A or SR 48968 one hour before exposure to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted. 3 Intracerebroventricular (i.c.v.) cannulae were placed in the lateral cerebral ventricles of anaesthetized guinea-pigs. Approximately one week later, the animals were dosed with CP-99,994 or SR 48212A (i.c.v.) and exposed to aerosols of capsaicin (0.3 mM) to elicit coughing. 4 Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was monitored from electromyograms of respiratory muscle activity. Cannulae were placed for intravenous (i.v.) or: in separate groups of animals, intravertebral arterial (i.a.) administration of CP-99,994, SR 48212A or SR 48968. Dose-response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED50 to i.a. ED50, known as the effective dose ratio (EDR). The EDR will be 20 or greater for a centrally active drug and less than 20 for a peripherally active drug. 5 In the guinea-pig, CP-99,994 (0.1-30 mg kg(-1), s.c.), SR 48212A (1.0-30 mg kg(-1), s.c.), and SR 48968 (0.3-3.0 mg kg(-1), s.c.) inhibited capsaicin-induced cough in a dose-dependent manner. Capsaicin-induced cough was also inhibited by i.c.v. administration of CP-99,994 (10 and 100 mu g) or SR 48212A (100 mu g). 6 In the cat, both CP-99,994 (0.0001-0.3 mg kg(-1), i.a., n=5; 0.003-3.0 mg kg(-1), i.v., n=5) and SR 48212A (0.003-1.0 mg kg(-1), i.a., n=5; 0.01-3.0 mg kg(-1), i.v., n=5) inhibited mechanically induced cough by either the i.v. or i.a. routes in a dose-dependent manner. SR 48968 (0.001-0.3 mg kg(-1), i.a., n=5; 0.03-1.0 mg kg(-1), i.v., n=5) inhibited cough when administered by the i.a., route in a dose-dependent manner, but had no effect by the i.v. route up to a dose of 1.0 mg kg(-1). Intravenous antitussive potencies (ED50, 95% confidence interval (CI)) of these compounds were: CP-99,994 (0.082 mg kg(-1), 95% CI 0.047-0.126), SR 48212A (2.3 mg kg(-1), 95% CI 0.5-20), and SR 48968 (>1.0 mg kg(-1), 95% CI not determined). The intra-arterial potencies of these compounds were: CP-99,994 (1.0 mu g kg(-1), 95% CI 0.4-1.8), SR 48212A (25 mu g kg(-1), 95% CI 13-52), and SR 48968 (8.0 mu g kg(-1), 95% CI 1-32). The derived EDRs for each compound were: CP-99,994, 82; SR 48212A, 92; and SR 48968, >125. 7 We concluded that CP-99,994 and SR 48968 inhibit cough in the guinea-pig and cat by a central site of action. In the cat, the antitussive action of these compounds appears to be solely by a central site.