The peripheral antinociceptive effect induced by morphine is associated with ATP-sensitive K+ channels

1 The effect of several K+ channel blockers such as glibenclamide, tolbutamide, charybdotoxin (ChTX), apamin, tetraethylammonium (TEA), 4-aminopyridine (4-AP) and cesium on the peripheral antinociceptive effect of morphine was evaluated by the paw pressure test in Wister rats. 2 The intraplantar administration of a carrageenan suspension (250 mu g) resulted in an acute inflammatory response and a decreased threshold to noxious pressure. Morphine administered locally into the paw (25, 50, 100 and 200 mu g) elicited a dose-dependent antinociceptive effect which was demonstrated to be mediated by a peripheral site up to the 100 mu g dose. 3 The selective blockers of ATP-sensitive K+ channels glibenclamide (20, 40 and 80 mu g paw(-1)) and tolbutamide (40, 80 and 160 mu g paw(-1)) antagonized the peripheral antinociception induced by morphine (100 mu g paw(-1)). 4 This effect was unaffected by ChTX (0.5, 1.0 and 2.0 mu g paw(-1)), a large conductance Ca2+-activated K+ channel blocker, or by apamin (2.5, 5.0 and 10.0 mu g paw(-1)), a selective blocker of a small conductance Ca2+-activated K+ channel. 5 Intraplantar administration of the non-specific K+ channel blockers TEA (160, 320 and 640 mu g), 4-AP (10, 50 and 100 mu g) and cesium (125, 250 and 500 mu g) also did not modify the peripheral antinociceptive effect of morphine. 6 These results suggest that the peripheral antinociceptive effect of morphine may result from activation of ATP-sensitive K+ channels,which may cause a hyperpolarization of peripheral terminals of primary afferents, leading to a decrease in action potential generation. In contrast, large conductance Ca2+-activated K+ channels, small conductance Ca2+-activated K+ channels as well as voltage-dependent K+ channels appear not to be involved in this transduction pathway.