Pentobarbital administered intracerebroventricularly antagonizes morphine-induced antinociception in mice

The purposes were to show that pentobarbital administered intracerebroventricularly (i.c.v.) antagonized the antinociceptive action of morphine given intrathecally in the tail-flick test in mice, determine whether this antagonistic action involved spinal release of dynorphin A (Dyn A) and demonstrate whether the mechanism involved gamma-aminobutyric acid (GABA) receptors. Previously, it was shown that midazolam given i.c.v. antagonizes morphine-induced antinociception by release of Dyn A in the spinal cord. This antagonism by midazolam is reversed by a variety of benzodiazepine/GABAA receptor complex antagonists given i.c.v. The results indicated that the antagonistic action of pentobarbital given i.c.v. was not due to release of Dyn A based on presumptive tests for Dyn A release. 1) In the tail-flick test, the opioid receptor antagonists, naloxone and nor-binaltorphimine intrathecally, did not reverse the antagonism. 2) Pretreatment with dynorphin antiserum and morphine had no effect. The effect of pentobarbital was inhibited by a benzodiazepine receptor antagonist, flumazenil, given i.c.v. but not by a GABA antagonist, bicuculline s.c. or a chloride ion channel antagonist, picrotoxin, i.c.v. In contrast, the duration of loss of the righting reflex from systematically administered pentobarbital was shortened by bicuculline and picrotoxin but not by flumazenil. These results taken together with the previous results on midazolam suggested that the antagonistic action of pentobarbital on morphine-induced antinociception appeared to involve different GABA receptors from those involved in release of Dyn A by midazolam and those involved in the pentobarbital-induced loss of the righting reflex.