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. ED50 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-1, s.c.) and 3-APPi (10 mg kg-1, s.c.) inhibited
capsaicin-induced
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 micrograms). Conversely, the
antitussive effect of 3-APPi was unaffected by i.c.v.
CGP 35348. However, systemic administration of
CGP 35348 (30 mg kg-1, s.c.) completely blocked the
antitussive activity of 3-APPi (10 mg kg-1, s.c.). In separate experiments
baclofen alone (1 microg, i.c.v.) inhibited
capsaicin-induced
cough by 78%. 3-APPi (10 and 100 microg, i.c.v.) had no effect on
capsaicin-induced
cough in the guinea pig.5. In the cat, potencies (ED50) of the standards and
GABA-B agonists by the i.v. route were:
codeine(0.34 mg kg-1),
BW443C (0.17 mg kg-1),
baclofen (0.63 mg kg-1) and 3-APPi (2.3 mg kg-1). Potencies of these drugs by the i.a. route were:
codeine, 0.013 mg kg-1;
BW443C, 0.06mg kg-1;
baclofen,0.016mg kg-1; and 3-APPi, 0.87 mg kg-1. 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.