Baclofen, an agonist at peripheral GABA B receptors, induces antinociception via activation of TEA‐sensitive potassium channels

Background and Purpose: Central anti‐nociceptive actions of baclofen involve activation of K + channels. Here we assessed what types of K + channel might participate in the peripheral anti‐nociception induced by baclofen. Experimental approach: Nociceptive thresholds to mechanical stimulation in rat paws treated with intraplantar prostaglandin E 2 .(PGE 2 ) to induce hyperalgesia were measured 3h after PGE 2 injection. Other agents were also given by intraplantar injection Key results: Baclofen elicited a dose‐dependent (15 ‐ 240 μg per paw) anti‐nociceptive effect. An intermediate dose of baclofen (60 μg) did not produce antinociception in the contralateral paw, showing its peripheral site of action. The GABA B receptor antagonist saclofen (12.5 ‐ 100 μg per paw) antagonized, in a dose‐dependent manner, peripheral antinociception induced by baclofen (60 μg), suggesting a specific effect. This antinociceptive action of baclofen was unaffected by bicuculline, GABA A receptor antagonist (80 μg per paw), or by (1,2,5,6 tetrahydropyridin‐4‐yl) methylphosphinic acid, GABA C receptor antagonist (20 μg per paw). The peripheral antinociception induced by baclofen (60 μg) was reversed, in a dose‐dependent manner, by the voltage‐dependent K + channel blockers tetraethylammonium (7.5 ‐ 30 μg per paw) and 4‐aminopyridine (2.5 ‐ 10 μg per paw). The blockers of other K + channels, glibenclamide (160 μg), tolbutamide (320 μg), charybdotoxin (2 μg), dequalinium (50 μg) and caesium (500 μg) had no effect. Conclusions and Implications: This study provides evidence that the peripheral antinociceptive effect of the GABA B receptor agonist baclofen results from the activation of tetraethylammonium‐sensitive K + channels. Other K + channels appear not to be involved. British Journal of Pharmacology (2006) 149 , 733–739. doi: 10.1038/sj.bjp.0706898