Antitussive effects of GABAB agonists in the cat and guinea-pig.
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- 30 mg kg-1, s.c.) inhibited the antitussive effect of baclofen (3.0 mg kg-1, s.c.). However, CGP 35348 (10 mg kg-1, s.c.) had no effect on the antitussive activity of codeine (30 mg kg-1, s.c.). The antitussive effect of baclofen was not influenced by the GABAA antagonist, bicuculline (3 mg kg-1, s.c.) or naloxone (0.3 mg kg-1, s.c.). 5. In the cat, baclofen (0.3-3.0 mg kg-1, i.v.) decreased mechanically-induced cough in a dose-dependent manner. In this model, baclofen (ED50 = 0.63 mg kg-1) 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-1, i.v.) and 3-aminopropylphosphonic acid (3 mg kg-1, 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.
Bolser
D C
DC
Schering-Plough Research Institute, Kenilworth, NJ 07033-0539.
Aziz
S M
SM
DeGennaro
F C
FC
Kreutner
W
W
Egan
R W
RW
Siegel
M I
MI
Chapman
R W
RW
D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology*; D001418:Baclofen / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002415:Cats; D003061:Codeine / Q000494:pharmacology; D003371:Cough / Q000139:chemically induced / Q000517:prevention & control; D003915:Dextromethorphan / Q000494:pharmacology; D004576:Electromyography; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D006168:Guinea Pigs; D007509:Irritants; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D012132:Respiratory Muscles / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000996:Antitussive Agents; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D007509:Irritants; D009943:Organophosphorus Compounds; C061388:3-aminopropylphosphinic acid; D005680:gamma-Aminobutyric Acid; D003915:Dextromethorphan; C066430:CGP 35348; D001418:Baclofen; D002211:Capsaicin; D003061:Codeine