Tiagabine antinociception in rodents depends on GABA(B) receptor activation: parallel antinociception testing and medial thalamus GABA microdialysis

The effects of a new antiepileptic drug, tiagabine, ( R)-N-[4,4-di-(3-methy lthien-2-yl)but-3-enyl] nipecotic acid hydrochloride, were studied in mice and rats in antinociceptive tests, using three kinds of noxious stimuli: me chanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). In vivo microdialysis was performed in parallel in awake, freely m oving rats in order to evaluate possible alterations in extracellular gamma -aminobutyric acid (GABA) levels in a pain-modulating region, the medial th alamus. Systemic administration of tiagabine, 30 mg kg(-1) i.p., increased nearly twofold the extracellular GABA levels in rats and increased signific antly the rat paw pressure nociceptive threshold in a time-correlated manne r. Dose-related significant tiagabine-induced antinociception was also obse rved at the doses of 1 and 3 mg kg(-)1 i.p. in the mouse hot plate and abdo minal constriction tests. The tiagabine antinociception was completely anta gonised by pretreatment with the selective GABA, receptor antagonist, CGP 3 5348, (3-aminopropyl-diethoxy methyl-phosphinic acid) (2.5 mu g/mouse or 25 mu g/rat i.c.v.), but not by naloxone (1 mg kg(-1) s.c.), both administere d 15 min before tiagabine. Thus, it is suggested that tiagabine causes anti nociception due to raised endogenous GABA levels which in turn activate GAB A(B) receptors. (C) 1999 Elsevier Science B.V. All rights reserved.