Comparison of the antinociceptive effect of gamma-aminobutyric acid (GABA) agonists: evidence for a cholinergic involvement.

The antinociceptive action of three classes of gamma-aminobutyric acid (GABA) agonists was examined in mice using the hot-plate and tail-immersion tests. A significant increase in reaction time was noted in the hot-plate test after treatment with the direct-acting GABA receptor agonists, kojic amine or 4,5,6,7-tetrahydroisoxazolo[5,4-C] pyridin-3-ol, with gamma-vinyl GABA, an inhibitor of GABA degradation, or with nipecotic acid ethyl ester, an inhibitor of high-affinity GABA transport. Studies with naloxone indicated that the increase in pain threshold was not mediated through the brain opiate system, although it was possible to reverse the antinociceptive effect of these drugs with atropine. Receptor binding experiments indicated that except for the ethyl ester of nipecotic acid, the GABA agonists have little affinity for the cholinergic muscarinic receptor site. Atropine, at a dose that completely blocked the antinociceptive action of kojic amine, was unable to attenuate the sedative effects of this drug. These findings suggest that, regardless of their mechanism, the three types of GABA agonists tested are capable of inducing an antinociceptive response in mice and that this action is apparently secondary to a GABA-mediated increase in brain cholinergic function.