Involvement of GABAergic systems in manifestation of pharmacological activity of desipramine.
We have conducted this study to elucidate the influence of GABAergic systems on manifestation of pharmacological activity of desipramine using both pharmacological and electrophysiological methods. Desipramine (20 mg/kg, i.p.) significantly blocked the adjuvant-induced thermal hyperalgesia, which was facilitated by treatment with the GABA(A) antagonist picrotoxin (2 mg/kg, i.p.) or the GABA(B) antagonist saclofen (2 mg/kg, 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 animals without adjuvant-induced inflammation. In a slice preparation of the hippocampus, 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 evoked in pyramidal neurons by Schaffer collateral stimulation. The inhibitory effect of GABA was facilitated by concurrent application of desipramine, carbamazepine or diazepam at a concentration of 5 x 10(-5)-2 x 10(-4) M. The 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 activate still more, and this phenomenon appears to be involved in manifestation of the pharmacological activity of desipramine such as antinociception.
Asahi
Y
Y
Bobath Memorial Hospital, Osaka, Japan.
Yonehara
N
N
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001418:Baclofen / Q000031:analogs & derivatives* / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology*; D005620:Freund's Adjuvant / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009118:Muscimol / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000929:Antidepressive Agents, Tricyclic; D001418:Baclofen; D003891:Desipramine; D005620:Freund's Adjuvant; D018756:GABA Antagonists; D009118:Muscimol; D010852:Picrotoxin; D005680:gamma-Aminobutyric Acid; C080629:saclofen