Respiratory effects ofbaclofen and3-aminopropylphosphinic acidinguinea-pigs

(i.c.v.) routewere examined on minuteventilation (V),tidal volume(VT)andrespiratory rate(f)duetoroom airandcarbondioxide (CO2)-enriched gas hyperventilation inconscious guinea-pigs. 2 Baclofen (0.3-10 mg kg-', s.c.) produced a dose-dependent inhibition ofV andfdueto room air andCO2inhalation. Themaximuminhibition ofroom airbreathing V was 85% ± 3andfwas 74% 3 at10mg kg-1, s.c.Themaximumeffects on C02-induced hyperventilation were 68% ± 9and51% 6, forV andfrespectively. Onlythehighest doseofbaclofen studied (10mg kg-')produced a significant inhibition ofVTduetoroom airbreathing (46%± 6)andCO2breathing (38%± 11). 3 3-APPi(0.3-100 mg kg-', s.c.) didnotaffect V, VTor fduetoroom airbreathing or CO2inhalation atany dosetested. Also, i.c.v. administration of3-APPi (100fig) didnotaffect ventilatory responses due toroom airbreathing or CO2inhalation. 4 Pretreatment withtheGABABantagonist, CGP353483-aminopropyl-(diethoxymethyl) phosphinic acid(3-30 mg kg',s.c.) blocked therespiratory depressant effects ofbaclofen (3mg kg-',s.c.) ina dose-related fashion. 5 Intracerebroventricular (i.c.v.) administration ofCGP 35348(50ptg) blocked therespiratory depressanteffects ofbaclofen. CGP 35348given aloneeither i.c.v. or s.c.hadno effects on respiration dueto room airor CO2inhalation. 6 Pretreatment witheither theGABAA antagonist bicuculline (30 mg kg-',s.c.) or theopioid antagonist, naloxone (1mg kg-', s.c.) hadno effect on therespiratory depressant action ofbaclofen (3mg kg', s.c.). 7 Theseresults showthatbaclofen inhibits ventilation duetoroom airbreathing, andattenuates the hyperventilation responsetoCO2inhalation. Theperipherally acting GABABagonist, 3-APPi hadno effect on ventilation. Thesefindings demonstrate thattherespiratory depressant effects ofbaclofen are duetoactivation ofCNS GABAB receptors andindicates thatonlyGABAB receptor agonists that penetrate intotheCNS may causerespiratory depression.