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

Abstract

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 micrograms) or SR 48212A (100 micrograms). 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 microgram kg-1, 95% CI 0.4-1.8), SR 48212A (25 micrograms kg-1, 95% CI 13-52), and SR 48968 (8.0 micrograms 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.