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.