The analgesic effect of dipyrone in peripheral tissue involves two different mechanisms: Neuronal KATP channel opening and CB1 receptor activation

Abstract

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 CB1 and CB2 cannabinoid receptors activation in the anti-hyperalgesic effect of dipyrone, 4-MAA or 4-AA. PGE2 (100ng/50µL/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 3h after its injection. Dipyrone, 4-MAA or 4-AA was administered 30min before the von Frey test. The selective CB1 receptor antagonist AM251, CB2 receptor antagonist AM630, cGMP inhibitor ODQ or KATP channel blocker glibenclamide were administered 30min before dipyrone, 4-MAA or 4-AA. The antisense-ODN against CB1 receptor expression was intrathecally administered once a day during four consecutive days. PGE2-induced mechanical hyperalgesia was inhibited by dipyrone, 4-MAA, and 4-AA in a dose-response manner. AM251 or ODN anti-sense against neuronal CB1 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 CB1, but not CB2 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 KATP opening.

The use of dipyrone (metamizol) as an analgesic in children: What is the evidence? A review

“…The spasmolytic effect of dipyrone might be explained through stimulation of the cannabis receptors . There is probably also a peripheral antinociceptive effect due to activation of ATP‐sensitive K‐channels . The antipyretic effect is achieved by COX‐2 inhibition …”

Cannabinoid CB1 receptors mediate the effects of dipyrone

“…demonstrated greater sensitivity at a 50°C than 55°C hotplate. Nevertheless, dos Santos et al . showed that, similar to dipyrone, the metabolites 4‐MAA and 4‐AA reduce PGE 2 ‐induced hyperalgesia in a nociceptive paw electronic pressure meter test.…”

Metamizole (Dipyrone) and the Liver: A Review of the Literature

“…Besides the metamizole metabolites mentioned above, which have been known for decades, 2 further metabolites have been identified more recently by liquid chromatography–mass spectrometry–based analyses after oral administration of metamizole to mice: arachidonoyl‐4‐MAA and arachidonoyl‐4‐AA, representing the arachidonoyl amides of 4‐MAA and 4‐AA, respectively . Furthermore, a total of 6 metabolites of metamizole could be detected in the urine of healthy volunteers after oral administration of metamizole.…”