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

Abstract

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 microg) resulted in an acute inflammatory response and a decreased threshold to noxious pressure. Morphine administered locally into the paw (25, 50, 100 and 200 microg) elicited a dose-dependent antinociceptive effect which was demonstrated to be mediated by a peripheral site up to the 100 microg dose. The selective blockers of ATP-sensitive K(+) channels glibenclamide (20, 40 and 80 microg paw(-1)) and tolbutamide (40, 80 and 160 microg paw(-1)) antagonized the peripheral antinociception induced by morphine (100 microg paw(-1)). This effect was unaffected by ChTX (0. 5, 1.0 and 2.0 microg paw(-1)), a large conductance Ca(2+)-activated K(+) channel blocker, or by apamin (2.5, 5.0 and 10.0 microg paw(-1)), a selective blocker of a small conductance Ca(2+)-activated K(+) channel. Intraplantar administration of the non-specific K(+) channel blockers TEA (160, 320 and 640 microg), 4-AP (10, 50 and 100 microg) and cesium (125, 250 and 500 microg) 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 Ca(2+)-activated K(+) channels, small conductance Ca(2+)-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

Figure 1

Effect of morphine on the nociceptive threshold in carrageenan-induced hyperalgesia in rats. Morphine (μg) was administered intraplantarly 2 h after the local administration of 100 μl of a carrageenan suspension (250 μg). Each column represents the mean±s.e.mean (n=10). ^*P<0.01 vs carrageenan+vehicle-injected control (Bonferroni's test).

Figure 2

Exclusion of a central antinociceptive effect of morphine. Morphine (μg) was administered into the right (R) or left (L) paw 2 h after carrageenan administration into both hind paws. Each column represents the mean±s.e.mean (n=10). ^*P<0.01 vs carrageenan+ vehicle-injected control (Bonferroni's test).

Figure 3

Antagonism induced by intraplantar administration of glibenclamide of the peripheral antinociception produced by morphine in hyperalgesic paws. Glibenclamide (μg) was administered 5 min before morphine (100 μg). Each column represents the mean±s.e.mean (n=5). ^* and # P<0.01 as compared to (Carrageenan+vehicles) and (Carrageenan+morphine+vehicle)- injected controls, respectively (Bonferroni's test).

Figure 4

Antagonism induced by intraplantar administration of tolbutamide of the peripheral antinociception produced by morphine in hyperalgesic paws. Tolbutamide (μg) was administered 5 min before morphine (100 μg). Each column represents the mean±s.e.mean (n=5). ^* and # P<0.01 as compared to (Carrageenan+vehicles) and (Carrageenan+morphine+vehicle)-injected controls, respectively (Bonferroni's test).

Figure 5

Effect of intraplantar administration of apamin and ChTX on the peripheral antinociception induced by morphine in hyperalgesic paws. Apamin and charybdotoxin (μg) were administered 45 min after morphine (100 μg). Each column represents the mean±s.e.mean (n=5). No statistically significant differences were detected between the groups treated with morphine+vehicle and morphine+apamin or ChTX in any case. ^*P<0.01 vs carrageenan+vehicle-injected control (Bonferroni's test).

Figure 6

Effect of intraplantar administration of 4-AP, TEA and Cesium on the peripheral antinociception induced by morphine in hyperalgesic paws. 4-AP, TEA and Cesium (μg paw⁻¹) were administered 45 min after morphine (100 μg paw⁻¹). Each column represents the mean±s.e.mean (n=5). No statistically significant differences between the groups treated with carrageenan+morphine+vehicle and carrageenan+morphine+4-AP, TEA or Cesium were found in any case. ^*P<0.01 vs carrageenan+vehicle-injected control (Bonferroni's test).