Evidence for a peripheral mechanism of action for the potentiation of the antinociceptive effect of morphine by dipyrone

The potentiation of the antinociceptive effect of morphine by dipyrone (metamizol) and the possible participation of a peripheral mechanism on such synergism were studied with the use of the formalin test in the rat. Nociception was induced by the intraplantar injection of diluted formalin (1%25) in the right hind paw. Local administration of either dipyrone or morphine in the site of injury produced a dose-dependent antinociceptive effect. When combined, noneffective doses of morphine (1.25 μg/paw) and dipyrone (100 μg/paw) produced a significantly greater antinociceptive effect compared with either drug alone or saline. The opioid antagonist naloxone partly reversed the effect of the dipyrone-morphine combination. On the other hand, the inhibitor of nitric oxide (NO) synthesis, N(G)-L-nitro-arginine methylester (L-NAME), but not its inactive isomer, D-NAME, completely antagonized the effect of the dipyrone-morphine combination. These results suggest that the potentiation of morphine-induced antinociception by dipyrone in the formalin test requires an important participation of local release of NO, activating the NO-cyclic GMP pathway at the peripheral level. (C) 2000 Elsevier Science Inc.

Cyclic GMP; Dipyrone; L-NAME; Morphine; Naloxone; Nitric oxide cyclic GMP; dipyrone; formaldehyde; morphine; n(g) nitro dextro arginine methyl ester; n(g) nitroarginine methyl ester; naloxone; nitric oxide; sodium chloride; analgesic activity; animal experiment; animal model; antinociception; article; controlled study; dose response; drug mechanism; drug potentiation; female; nonhuman; pain; prostaglandin synthesis inhibition; rat; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclic GMP; Dipyrone; Drug Synergism; Female; Morphine; Naloxone; Narcotics; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Animalia

VIVO