ANTITUSSIVE EFFECTS OF GABA(B) AGONISTS IN THE CAT AND GUINEA-PIG

1 GABA(B) agonists inhibit neuronal processes which are important in t he pathogenesis of airway disease, such as bronchospasm Cough is a pro minent symptom of pulmonary disease, but the effects of GABA(B) agonis ts on this airway reflex are unknown. Experiments were conducted to de termine the antitussive effect of GABA(B) receptor agonists in compari son to the known antitussive agents, codeine and dextromethorphan. 2 U nanaesthetized guinea-pigs were exposed to aerosols of 0.3 mm capsaici n to elicit coughing, which was detected with a microphone and counted . Cough also was produced in anaesthetized cats by mechanical stimulat ion of the intrathoracic trachea and was recorded from electromyograms of respiratory muscle activity. 3 In guinea-pigs, the GABA(B) agonist s baclofen and 3-aminopropyl-phosphinic acid (3-APPi) produced dose-de pendent inhibition of capsaicin-induced cough when administered by sub cutaneous or inhaled routes- The potencies of baclofen and 3-APPi comp ared favourably with codeine and dextromethorphan. 4 The GABA(B) antag onist, CGP 35348 (0.3- 30 mg kg-1, s.c.) inhibited the antitussive eff ect 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 G ABA(A) antagonist, bicuculline (3 mg kg-1, s.c.) or naloxone (0.3 mg k g-1, s.c.). 5 In the cat, baclofen (0.3-3.0 mg kg-1, i.v.) decreased m echanically-induced cough in a dose-dependent manner. In this model, b aclofen (ED50 = 0.63 mg kg-1) was less potent than either codeine or d extromethorphan. The antitussive effect of baclofen in the cat was ant agonized by the GABA(B) antagonists, CGP 35348 (10 mg kg-1, i.v.) and 3-aminopropylphosphonic acid (3 mg kg-1, i.v.). 6 We show that baclofe n and 3-APPi have antitussive effects in the guinea-pig and cat and th ese effects are mediated by GABA(B) receptors.