GABAA receptor antagonists reduce acute opiate withdrawal in isolated tissue

1. The effect exerted by GABAA receptor agonists and antagonists on the acute opiate withdrawal induced by mu and k receptor agonists were investigated in vitro. 2. Following a 4 min in vitro exposure to morphine (less selective mu agonist), DAGO (highly selective mu agonist) and U50-488H (highly selective k agonist) the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. 3. Bicuculline (1 x 10(-5)-5 x 10(-5)-1 x 10(-4) M), a GABAA receptor antagonist, injected 10 min before or after the opioid agonists was able dose-dependently to antagonize the naloxone-induced contracture after exposure to mu (morphine and DAGO) and k (U50-488H) opiate agonists. 4. Furthermore, picrotoxin (1 x 10(-5)-5 x 10(-5)-1 x 10(-4) M), an antagonist of GABA-linked chloride channels, was able to exert the same effects. 5. Muscimol (1 x 10(-5)-5 x 10(-5)-1 x 10(-4) M), a GABAA receptor agonist, was able to increase dose dependently both mu and k opiate withdrawal. 6. The data indicate that both GABAA receptor agonists and antagonists are able to control opiate withdrawal in vitro suggesting an important functional interaction between GABAergic system and the opioid withdrawal both at the mu and k receptor level.