Dibutyryl-cyclic GMP induces peripheral antinociception via activation of ATP-sensitive K+ channels in the rat PGE2-induced hyperalgesic paw

摘要

class="enumerated" style="list-style-type:decimal">Using the rat paw pressure test, in which increased sensitivity is induced by intraplantar injection of prostaglandin E2, we studied the action of several K⁺ channel blockers in order to determine what types of K⁺ channels could be involved in the peripheral antinociception induced by dibutyrylguanosine 3 : 5′-cyclic monophosphate (DbcGMP), a membrane permeable analogue of cyclic GMP.DbcGMP elicited a dose-dependent (50, 75, 100 and 200 μg paw⁻¹) peripheral antinociceptive effect. The effect of the 100 μg dose of DbcGMP was considered to be local since only a higher dose (300 μg paw⁻¹) produced antinociception in the contralateral paw.The antinociceptive effect of DbcGMP (100 μg paw⁻¹) was dose-dependently antagonized by intraplantar administration of the sulphonylureas tolbutamide (20, 40 and 160 μg) and glibenclamide (40, 80 and 160 μg), selective blockers of ATP-sensitive K⁺ channels.Charybdotoxin (2 μg paw⁻¹), a selective blocker of high conductance Ca²⁺-activated K⁺ channels, and apamin (10 μg paw⁻¹), a selective blocker of low conductance Ca²⁺-activated K⁺ channels, did not modify the peripheral antinociception induced by DbcGMP.Tetraethylammonium (2 mg paw⁻¹), 4-aminopyridine (200 μg paw⁻¹) and cesium (800 paw⁻¹), non-selective voltage-gated potassium channel blockers, also had no effect.Based on this experimental evidence, we conclude that the activation of ATP-sensitive K⁺ channels could be the mechanism by which DbcGMP induces peripheral antinociception, and that Ca²⁺-activated K⁺ channels and voltage-dependent K⁺ channels appear not to be involved in the process.