Involvement of chloride channel coupled GABA C receptors in the peripheral antinociceptive effect induced by GABA C receptor agonist cis-4-aminocrotonic acid

Abstract

We investigated the effect of chloride and potassium channel blockers on the antinociception induced by GABA C receptor agonist CACA ( cis-4-aminocrotonic acid) using the paw pressure test, in which pain sensitivity was increased by an intraplantar injection (2 μg) of prostaglandin E 2 (PGE 2). CACA administered locally into the right hindpaw (25, 50 and 100 μg/paw) elicited a dose-dependent antinociceptive effect which was demonstrated to be local, since only higher doses produced an effect when injected in the contralateral paw. The GABA C receptor antagonist (1,2,5,6 tetrahydropyridin-4-yl) methylphosphinic acid (TPMPA; 5, 10 and 20 μg/paw) antagonized, in a dose-dependent manner, the peripheral antinociception induced by CACA (100 μg), suggesting a specific effect. This effect was reversed by the chloride channel coupled receptor blocker picrotoxin (0.8 μg/paw). Glibenclamide (160 μg) and tolbutamide (320 μg), blockers of ATP-sensitive potassium channels, charybdotoxin (2 μg), a large-conductance potassium channel blocker, dequalinium (50 μg), a small-conductance potassium channel blocker, and cesium (500 μg), a non-specific potassium channel blocker did not modify the peripheral antinociception induced by CACA. This study provides evidence that activation of GABA C receptors in the periphery induces antinociception, that this effect results from the activation of chloride channel coupled GABA C receptors and that potassium channels appear not to be involved.