ANTAGONISM OF L-BACLOFEN-INDUCED ANTINOCICEPTION BY CGP-35348 IN THE SPINAL-CORD OF THE RAT

This study examined the potency and selectivity of the GABA(B) receptor antagonist CGP 35348 (3-amino-propyl(diethoxymethyl)phosphinic acid in the spinal cord of the rat. Intrathecal (i.t.) administration of 3-30 mug CGP 35348 produced a dose-dependent antagonism of the antinociception produced by i.t. administered L-baclofen. Increasing doses of CGP 35348 produced progressive, rightward parallel shifts in the dose-effect relationship of L-baclofen in both the tail flick and hot plate tests. However, in the tail flick test, the magnitude of the shift was not proportional to the dose of CGP 35348 such that doses greater than 10 mug i.t. produced no further antagonism. Schild analysis using all three doses of CGP 35348 yielded a slope of -0.45. However, if the Schild analysis was confined to the two lowest doses of CGP 35348 at which progressive shifts were obtained, a slope of -0.91 and an apparent pA2 value of 9.3 were obtained. An apparent pA2 value of 9.0 was also obtained in the hot plate test using the two lowest doses of CGP 35348. These data suggest that CGP 35348 is a competitive GABA(B) receptor antagonist at low concentrations. However, the failure to observe greater antagonism at higher doses of CGP 35348 suggests that this drug may exhibit additional properties at higher concentrations that can mask or prevent the occurrence of further antagonism. In contrast, the antinociception produced by i.t. administration of the GABA(A) receptor agonist isoguvacine was not antagonized by 30 mug i.t. CGP 35348, a dose that shifted the dose-effect relationship of L-baclofen 10-fold to the right. These data suggest that CGP 35348 is a potent and selective antagonist of spinal GABA(B) receptors in the rat.