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

• Published in: Life sciences (1973) 2004-04, Vol.74 (20), p.2577-2591
• Main Authors: Alves, Daniela P, Tatsuo, Maria A.F, Leite, Romulo, Duarte, Igor D.G
• Format: Article
• Language: English
• Subjects: Analgesia; Animals; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Antinociception; Diclofenac; Diclofenac - metabolism; Dinoprostone - metabolism; Dose-Response Relationship, Drug; Enzyme Inhibitors - metabolism; Glyburide - metabolism; Hyperalgesia - chemically induced; Indomethacin - metabolism; K + channel blockers; K + channels; Male; Naloxone - metabolism; Narcotic Antagonists - metabolism; Pain Measurement; Potassium Channel Blockers - metabolism; Potassium Channels - metabolism; Rats; Rats, Wistar; Tolbutamide - metabolism
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2003.10.012

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 μg) of prostaglandin E 2. Diclofenac administered locally into the right hindpaw (25, 50, 100 and 200 μg) 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 μg/paw) was antagonized in a dose-dependent manner by intraplantar administration of the sulphonylureas glibenclamide (40, 80 and 160 μg) and tolbutamide (80, 160 and 320 μg), 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 μg/paw), a typical cyclo-oxygenase inhibitor, over carrageenin-induced hyperalgesia was not affected by this treatment. Charybdotoxin (2 μg/paw), a blocker of large conductance Ca 2+-activated K + channels and dequalinium (50 μg/paw), a selective blocker of small conductance Ca 2+-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 μg) and 4-aminopyridine (100 μg) or cesium (500 μg), a non-specific K + channel blocker. The peripheral antinociceptive effect induced by diclofenac was antagonized by N G-Nitro L-arginine (NOarg, 50 μg/paw), a NO synthase inhibitor and methylene blue (MB, 500 μg/paw), a guanylate cyclase inhibitor, and this antagonism was reversed by diazoxide (300 μg/paw), an ATP-sensitive K + channel opener. We also suggest that an endogenous opioid system may not be involved since naloxone (50 μg/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 Ca 2+-activated K + channels, voltage-dependent K + channels as well as endogenous opioids appear not to be involved in the process.