Irreversible inhibitors of GABA transaminase induce antinociceptive effects and potentiate morphine

Abstract

The irreversible inhibitors of GABA-transaminase, γ-acetylenic GABA and γ-vinyl GABA, were examined for antinociceptive actions in rodents. An antinociceptive effect unaccompanied by ataxia was demonstrated in mice on the 52°C hot-plate and in rats in a tail-stimulation procedure and was maximal at 4–6 hr after drug administration, which correlates temporally with reported maximal increases of brain GABA. The antinociceptive effect was antagonized by a subconvulsive dose of bicuculine (0.5 mg/kg, i.p.) in rats, but could not be prevented by naloxone (1 mg/kg, i.p.) in mice. Only the (+)-stereoisomer γ-vinyl GABA, active as a GABA-transaminase inhibitor, was antinociceptive. The effects appear to be causally related to elevated cerebral GABA levels. The profile of these agents in the tail stimulation test in rats suggests a specific antinociceptive effect since vocalization and vocalization after-discharge were similarly affected. The analgesic actions of morphine in mice on the 56°C hot-plate were enhanced 5 hr after the administration of γ-acetylenic GABA or γ-vinyl GABA. The compounds did not alter the naloxone-precipitated morphine withdrawal syndrome in the rat. It is concluded that γ-acetylenic GABA and γ-vinyl GABA can produce distinct antinociceptive effects in rats and mice related to increased brain GABA levels, but which are not opioid-like in nature.