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

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 Wistar rats. The intraplantar administration of a carrageenan suspension (250 μg) resulted in an acute inflammatory response and a decreased threshold to noxious pressure. Morphine administered locally into the paw (25, 50, 100 and 200 μg) elicited a dose‐dependent antinociceptive effect which was demonstrated to be mediated by a peripheral site up to the 100 μg dose. The selective blockers of ATP‐sensitive K+ channels glibenclamide (20, 40 and 80 μg paw−1) and tolbutamide (40, 80 and 160 μg paw−1) antagonized the peripheral antinociception induced by morphine (100 μg paw−1). This effect was unaffected by ChTX (0.5, 1.0 and 2.0 μg paw−1), a large conductance Ca2+‐activated K+ channel blocker, or by apamin (2.5, 5.0 and 10.0 μg paw−1), a selective blocker of a small conductance Ca2+‐activated K+ channel. Intraplantar administration of the non‐specific K+ channel blockers TEA (160, 320 and 640 μg), 4‐AP (10, 50 and 100 μg) and cesium (125, 250 and 500 μg) also did not modify the peripheral antinociceptive effect of morphine. 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. British Journal of Pharmacology (2000) 129, 110–114; doi:10.1038/sj.bjp.0703038