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

• Published in: British journal of pharmacology Vol. 149; no. 6; pp. 733 - 739
• Main Authors: Reis, G M L, Duarte, I D G
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-11-2006; Nature Publishing; Nature Publishing Group
• Subjects: 4‐aminopyridine; Analgesics - pharmacology; Animals; baclofen; Baclofen - analogs & derivatives; Baclofen - pharmacology; Bicuculline - pharmacology; Biological and medical sciences; Cesium - pharmacology; Charybdotoxin - pharmacology; Dequalinium - pharmacology; GABA Agonists - pharmacology; GABA-B Receptor Agonists; GABAB receptor; Glyburide - pharmacology; K+ channel; Male; Medical sciences; peripheral antinociception; Pharmacology. Drug treatments; Potassium Channels - drug effects; Rats; Rats, Wistar; Research Papers; saclofen; sulphonylureas; tetraethylammonium; Tetraethylammonium - pharmacology; Tolbutamide - pharmacology; peripheral antinociception; Agonist; GABAB receptor; Muscle relaxant; Gabaergic agonist; Ionic channel; sulphonylureas; Inorganic element; saclofen; K+ channel; Analgesia; 4-aminopyridine; Antispasmodic agent; tetraethylammonium; Baclofen; Sulfonylureas; Gabaergic receptor B; Potassium
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706898

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 GABAB 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, GABAA receptor antagonist (80 μg per paw), or by (1,2,5,6 tetrahydropyridin‐4‐yl) methylphosphinic acid, GABAC 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 GABAB 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