Involvement of GABAergic systems in manifestation of pharmacological activity of desipramine

We have conducted this study to elucidate the influence of GABAergic system s on manifestation of pharmacological activity of desipramine using both ph armacological and electrophysiological methods. Desipramine (20 mg/kg, i.p. ) significantly blocked the adjuvant-induced thermal hyperalgesia, which wa s facilitated by treatment with the GABA(A) antagonist picrotoxin (2 mg/kg, i.p.) or the GABA(B) antagonist saclofen (2 mg/k-g, i.p.). This analgesic effect of desipramine was antagonized by post-treatment with picrotoxin or saclofen. However, none of these compounds showed any effect in normal anim als without adjuvant-induced inflammation. In a slice preparation of the hi ppocampus, treatment with GABA (10(-5) - 5 x 10(-4) M), baclofen (10(-5) - 10(-4) M) or muscimol (10(-5) - 10(-4) M) inhibited the field potential evo ked in pyramidal neurons by Schaffer collateral stimulation. The inhibitory effect of GABA was facilitated by concurrent application of desipramine, c arbamazepine or diazepam at a concentration of 5 x 10(-5) - 2 x 10(-4) M. T he rank of order of facilitation is: desipramine > carbamazepine > diazepam . Desipramine also enhanced the inhibitory effect of baclofen and muscimol. These results suggest that desipramine causes GABAergic systems to activat e still more, and this phenomenon appears to be involved in manifestation o f the pharmacological activity of desipramine such as antinociception.