Diclofenac-induced peripheral antinociception is associated with ATP-sensitive K+ channels activation

In order to investigate to the contribution of K+ channels on the peripheral antinociception induced by diclofenac, we evaluated the effect of several K+ channel blockers, using the rat paw pressure test, in which sensitivity is increased by intraplantar injection (2 mug) of prostaglandin E-2. Diclofenac administered locally into the right hindpaw (25, 50, 100 and 200 mug) elicited a dose-dependent antinociceptive effect which was demonstrated to be local, since only higher doses produced an effect when injected in the contralateral paw. This blockade of PGE(2) mechanical hyperalgesia induced by diclofenac (100 mug/paw) was antagonized in a dose-dependent manner by intraplantar administration of the sulphonylureas glibenclamide (40, 80 and 160 mug) and tolbutamide (80, 160 and 320 mug), specific blockers of ATP-sensitive K+ channels, and it was observed even when the hyperalgesic agent used was carrageenin, while the antinociceptive action of indomethacin (200 mug/ paw), a typical cyclo-oxygenase inhibitor, over carrageenin-induced hyperalgesia was not affected by this treatment. Charybdotoxin (2 mug/paw), a blocker of large conductance Ca2+-activated K+ channels and dequalinium (50 mug/paw), a selective blocker of small conductance Ca2+-activated K+ channels, did not modify the effect of diclofenac. This effect was also unaffected by intraplantar administration of non-specific voltage-dependent K+ channel blockers tetraethylammonium. (1700 mug) and 4-aminopyridine (100 mug) or cesium (500 mug), a non-specific K+ channel blocker. The peripheral antinociceptive effect induced. by diclofenac was antagonized by N-G-Nitro L-arginine (NOarg, 50 mug/paw), a NO synthase inhibitor and methylene blue (MB, 500 mug/paw), a guanylate cyclase inhibitor, and this antagonism was reversed by diazoxide (300 mug/paw), an ATP-sensitive K+ channel opener. We also suggest that an endogenous opioid system may not be involved since naloxone (50 mug/paw) did not affect diclofenac-induced antinociception in the PGE(2)-induced hyperalgesia model. This study provides evidence that the peripheral antinociceptive effect of diclofenac may result from activation of ATP-sensitive K+ channels, possible involving stimulation of L-arginine/NO/cGMP pathway, while Ca2+-activated K+ channels, voltage-dependent K+ channels as well as endogenous opioids appear not to be involved in the process. (C) 2004 Elsevier Inc. All rights reserved.