The analgesic effect of dipyrone in peripheral tissue involves two different mechanisms: Neuronal K sub(ATP) channel opening and CB sub(1) receptor activation

• Published in: European journal of pharmacology Vol. 741; pp. 124 - 131
• Main Authors: Santos, Gilson Goncalves dos, Dias, Elayne Vieira, Teixeira, Juliana Maia, Athie, Maria Carolina Pedro, Bonet, Ivan Jose Magayewski, Tambeli, Claudia Herrera, Parada, Carlos Amilcar
• Format: Journal Article
• Language: English
• Published: 01.01.2014
• ISSN: 0014-2999
• DOI: 10.1016/j.ejphar.2014.07.019

Dipyrone (metamizole) is an analgesic pro-drug used to control moderate pain. It is metabolized in two major bioactive metabolites: 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA). The aim of this study was to investigate the participation of peripheral CB sub(1) and CB sub(2) cannabinoid receptors activation in the anti-hyperalgesic effect of dipyrone, 4-MAA or 4-AA. PGE sub(2) (100 ng/50 mu L/paw) was locally administered in the hindpaw of male Wistar rats, and the mechanical nociceptive threshold was quantified by electronic von Frey test, before and 3 h after its injection. Dipyrone, 4-MAA or 4-AA was administered 30 min before the von Frey test. The selective CB sub(1) receptor antagonist AM251, CB sub(2) receptor antagonist AM630, cGMP inhibitor ODQ or K sub(ATP) channel blocker glibenclamide were administered 30 min before dipyrone, 4-MAA or 4-AA. The antisense-ODN against CB sub(1) receptor expression was intrathecally administered once a day during four consecutive days. PGE sub(2)-induced mechanical hyperalgesia was inhibited by dipyrone, 4-MAA, and 4-AA in a dose-response manner. AM251 or ODN anti-sense against neuronal CB sub(1) receptor, but not AM630, reversed the anti-hyperalgesic effect mediated by 4-AA, but not by dipyrone or 4-MAA. On the other hand, the anti-hyperalgesic effect of dipyrone or 4-MAA was reversed by glibenclamide or ODQ. These results suggest that the activation of neuronal CB sub(1), but not CB sub(2) receptor, in peripheral tissue is involved in the anti-hyperalgesic effect of 4-aminoantipyrine. In addition, 4-methylaminoantipyrine mediates the anti-hyperalgesic effect by cGMP activation and K sub(ATP) opening.