Respiratory effects of baclofen and 3-aminopropylphosphinic acid in guinea-pigs.
1. The effects of the GABAB receptor agonists, baclofen and 3-aminopropylphosphinic acid (3-APPi) given by the subcutaneous or intracerebroventricular (i.c.v.) route were examined on minute ventilation (V), tidal volume (VT) and respiratory rate (f) due to room air and carbon dioxide (CO2)-enriched gas hyperventilation in conscious guinea-pigs. 2. Baclofen (0.3-10 mg kg-1, s.c.) produced a dose-dependent inhibition of V and f due to room air and CO2 inhalation. The maximum inhibition of room air breathing V was 85% +/- 3 and f was 74% +/- 3 at 10 mg kg-1, s.c. The maximum effects on CO2-induced hyperventilation were 68% +/- 9 and 51% +/- 6, for V and f respectively. Only the highest dose of baclofen studied (10 mg kg-1) produced a significant inhibition of VT due to room air breathing (46% +/- 6) and CO2 breathing (38% +/- 11). 3. 3-APPi (0.3-100 mg kg-1, s.c.) did not affect V, VT or f due to room air breathing or CO2 inhalation at any dose tested. Also, i.c.v. administration of 3-APPi (100 micrograms) did not affect ventilatory responses due to room air breathing or CO2 inhalation. 4. Pretreatment with the GABAB antagonist, CGP 35348 3-aminopropyl-(diethoxymethyl) phosphinic acid (3-30 mg kg-1, s.c.) blocked the respiratory depressant effects of baclofen (3 mg kg-1, s.c.) in a dose-related fashion. 5. Intracerebroventricular (i.c.v.) administration of CGP 35348 (50 micrograms) blocked the respiratory depressant effects of baclofen. CGP 35348 given alone either i.c.v. or s.c. had no effects on respiration due to room air or CO2 inhalation.6. Pretreatment with either the GABAA antagonist bicuculline (30 mg kg-1, s.c.) or the opioid antagonist, naloxone (1 mg kg-1, s.c.) had no effect on the respiratory depressant action of baclofen(3 mg kg-1, s.c.).7. These results show that baclofen inhibits ventilation due to room air breathing, and attenuates the hyperventilation response to CO2 inhalation. The peripherally acting GABAB agonist, 3-APPi had no effect on ventilation. These findings demonstrate that the respiratory depressant effects of baclofen are due to activation of CNS GABAB receptors and indicates that only GABAB receptor agonists that penetrate into the CNS may cause respiratory depression.
Hey
J A
JA
Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA.
Mingo
G
G
Bolser
D C
DC
Kreutner
W
W
Krobatsch
D
D
Chapman
R W
RW
D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D001418:Baclofen / Q000008:administration & dosage / Q000494:pharmacology*; D001640:Bicuculline / Q000008:administration & dosage / Q000494:pharmacology; D002245:Carbon Dioxide / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D006168:Guinea Pigs; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D012123:Pulmonary Ventilation / Q000187:drug effects; D012119:Respiration / Q000187:drug effects*; D013990:Tidal Volume / Q000187:drug effects
D018755:GABA Agonists; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; C061388:3-aminopropylphosphinic acid; D002245:Carbon Dioxide; D009270:Naloxone; C066430:CGP 35348; D001418:Baclofen; D001640:Bicuculline