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Respiratory effects of baclofen and 3‐aminopropylphosphinic acid in guinea‐pigs
Author(s) -
Hey John A.,
Mingo Garfield,
Bolser Donald C.,
Kreutner William,
Krobatsch Dawn,
Chapman Richard W.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb13265.x
Subject(s) - hyperventilation , tidal volume , baclofen , respiratory rate , respiratory minute volume , anesthesia , ventilation (architecture) , inhalation , respiratory system , chemistry , pharmacology , depressant , medicine , heart rate , agonist , biochemistry , receptor , blood pressure , mechanical engineering , engineering
1 The effects of the GABA B receptor agonists, baclofen and 3‐aminopropylphosphinic acid (3‐APPi) given by the subcutaneous or intracerebroventricular (i.c.v.) route were examined on minute ventilation (), tidal volume (V T ) and respiratory rate (f) due to room air and carbon dioxide (CO 2 )‐enriched gas hyperventilation in conscious guinea‐pigs. 2 Baclofen (0.3–10 mg kg −1 , s.c.) produced a dose‐dependent inhibition of and f due to room air and CO 2 inhalation. The maximum inhibition of room air breathing was 85% ± 3 and f was 74% ± 3 at 10 mg kg −1 , s.c. The maximum effects on CO 2 ‐induced hyperventilation were 68% ± 9 and 51% ± 6, for and f respectively. Only the highest dose of baclofen studied (10 mg kg −1 ) produced a significant inhibition of V T due to room air breathing (46% ± 6) and CO 2 breathing (38% ± 11). 3 3‐aPPi (0.3–100 mg kg −1 , s.c.) did not affect , V T or f due to room air breathing or CO 2 inhalation at any dose tested. Also, i.c.v. administration of 3‐aPPi (100 μg) did not affect ventilatory responses due to room air breathing or CO 2 inhalation. 4 Pretreatment with the GABA B 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 μg) 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 CO 2 inhalation. 6 Pretreatment with either the GABA A 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 CO 2 inhalation. The peripherally acting GABA B agonist, 3‐APPi had no effect on ventilation. These findings demonstrate that the respiratory depressant effects of baclofen are due to activation of CNS GABA B receptors and indicates that only GABA B receptor agonists that penetrate into the CNS may cause respiratory depression.