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 E₂.(PGE₂) to induce hyperalgesia were measured 3h after PGE₂ 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.

DOI: 10.1038/sj.bjp.0706898

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