1 The purpose of this study was to investigate the antitussive activity and sites of action of the NK 1 and NK 2 tachykinin receptor antagonists, 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 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. ED 50 to i.a. ED 50 , known as the e ective 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 71 , s.c.), SR 48212A (1.0 ± 30 mg kg 71 , s.c.), and SR 48968 (0.3 ± 3.0 mg kg 71 , s.c.) inhibited capsaicin-induced cough in a dose-dependent manner. Capsaicininduced cough was also inhibited by i.c.v. administration of CP-99,994 (10 and 100 mg) or SR 48212A (100 mg). 6 In the cat, both CP-99,994 (0.0001 ± 0.3 mg kg 71 , i.a., n=5; 0.003 ± 3.0 mg kg 71 , i.v., n=5) and SR 48212A (0.003 ± 1.0 mg kg 71 , i.a., n=5; 0.01 ± 3.0 mg kg 71 , 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 71 , i.a., n=5; 0.03 ± 1.0 mg kg 71 , i.v., n=5) inhibited cough when administered by the i.a. route in a dosedependent manner, but had no e ect by the i.v. route up to a dose of 1.0 mg kg 71 . Intravenous antitussive potencies (ED 50 , 95% con®dence interval (CI)) of these compounds were: CP-99,994 (0.082 mg kg 71 , 95% CI 0.047 ± 0.126), SR 48212A (2.3 mg kg 71 , 95% CI 0.5 ± 20), and SR 48968 (41.0 mg kg 71 , 95% CI not determined). The intra-arterial potencies of these compounds were: CP-99,994 (1.0 mg kg 71 , 95% CI 0.4 ± 1.8), SR 48212A (25 mg kg 71 , 95% CI 13 ± 52), and SR 48968 (8.0 mg kg 71 , 95% CI 1 ± 32). The derived EDRs for each compound were: 994, 82; SR 48212A, 92; and SR 48968, 4125. 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.

1 The GABA-B receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPi) have antitussive activity in the cat and guinea pig. The purpose of this study was to investigate the sites of action of these GABA-B receptor agonists to inhibit the cough reflex. 2 Single intracerebroventricular (i.c.v.) cannulas were placed in the lateral ventricles of anaesthetized guinea pigs. Approximately 1 week later, the animals were exposed to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted. 3 Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was recorded from electromyograms of respiratory muscle activity. Cannulas were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of baclofen, 3-APPi, the centrally active antitussive drug codeine or the peripherally active antitussive drug BW443c. Dose-response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED" to i.a. ED50, known as the effective dose ratio (EDR). The EDR will be 20 or greater for a centrally acting drug. 4 In the guinea pig, baclofen (3 mg kg-', s.c.) and 3-APPi (10 mg kg-', s.c.) inhibited capsaicininduced cough by 50% and 35% respectively. The antitussive activity of baclofen was completely blocked by i.c.v. administration of the GABA-B receptor antagonist CGP 35348 (10 jig). Conversely, the antitussive effect of 3-APPi was unaffected by i.c.v. CGP 35348. However, systemic administration of CGP 35348 (30 mg kg-', s.c.) completely blocked the antitussive activity of 3-APPi (10 mg kg-', s.c.). In separate experiments baclofen alone (1 gpg, i.c.v.) inhibited capsaicin-induced cough by 78%. 3-APPi (10 and 100 gg, i.c.v.) had no effect on capsaicin-induced cough in the guinea pig. 5In the cat, potencies (ED50) of the standards and GABA-B agonists by the i.v. route were: codeine (0.34 mg kg-'), BW443C (0.17 mg kg-'), baclofen (0.63 mg kg-') and 3-APPi (2.3 mg kg-'). Potencies of these drugs by the i.a. route were: codeine, 0.013 mg kg-'; BW443C, 0.06mg kg-'; baclofen, 0.016mg kg-'; and 3-APPi, 0.87 mg kg'. The EDRs for each drug were: codeine, 26; BW443C, 3; baclofen, 39; and 3-APPi, 3. 6 We conclude that in both the cat and guinea pig baclofen inhibits cough by a central site of action, while 3-APPi inhibits cough by a peripheral site of action.

1 GABAB agonists inhibit neuronal processes which are important in the pathogenesis of airway disease, such as bronchospasm. Cough is a prominent symptom of pulmonary disease, but the effects of GABAB agonists on this airway reflex are unknown. Experiments were conducted to determine the antitussive effect of GABAB receptor agonists in comparison to the known antitussive agents, codeine and dextromethorphan. 2 Unanaesthetized guinea-pigs were exposed to aerosols of 0.3 mM capsaicin to elicit coughing, which was detected with a microphone and counted. Cough also was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was recorded from electromyograms of respiratory muscle activity. 3 In guinea-pigs, the GABAB agonists baclofen and 3-aminopropyl-phosphinic acid (3-APPi) produced dose-dependent inhibition of capsaicin-induced cough when administered by subcutaneous or inhaled routes. The potencies of baclofen and 3-APPi compared favourably with codeine and dextromethorphan.4 The GABAB antagonist, CGP 35348 (0.3-30mg kg-', s.c.) inhibited the antitussive effect of baclofen (3.0mgkg-', s.c.). However, CGP 35348 (10mgkg-', s.c.) had no effect on the antitussive activity of codeine (30mgkg-', s.c.). The antitussive effect of baclofen was not influenced by the GABAA antagonist, bicuculline (3mgkg-', s.c.) or naloxone (0.3mgkg'1, s.c.). 5 In the cat, baclofen (0.3-3.0 mg kg-', i.v.) decreased mechanically-induced cough in a dosedependent manner. In this model, baclofen (ED_0 = 0.63 mg kg-l) was less potent than either codeine or dextromethorphan. The antitussive effect of baclofen in the cat was antagonized by the GABAB antagonists, CGP 35348 (10 mg kg', i.v.) and 3-aminopropylphosphonic acid (3 mg kg', i.v.). 6 We show that baclofen and 3-APPi have antitussive effects in the guinea-pig and cat and these effects are mediated by GABAB receptors.

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