title: The analgesic effect of dipyrone in peripheral tissue involves two different mechanisms: neuronal K(ATP) channel opening and CB(1) 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.
authors: Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, CP 6109, CEP: 13083-970 Campinas, SP, Brazil.
authors: Gilson Gonçalves
authors: GG
authors: dos Santos
authors: Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, CP 6109, CEP: 13083-970 Campinas, SP, Brazil.
authors: Elayne Vieira
authors: EV
authors: Dias
authors: Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, CP 6109, CEP: 13083-970 Campinas, SP, Brazil.
authors: Juliana Maia
authors: JM
authors: Teixeira
authors: Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, CP 6109, CEP: 13083-970 Campinas, SP, Brazil.
authors: Maria Carolina Pedro
authors: MC
authors: Athie
authors: Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, CP 6109, CEP: 13083-970 Campinas, SP, Brazil.
authors: Ivan José Magayewski
authors: IJ
authors: Bonet
authors: Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, CP 6109, CEP: 13083-970 Campinas, SP, Brazil.
authors: Cláudia Herrera
authors: CH
authors: Tambeli
authors: Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, CP 6109, CEP: 13083-970 Campinas, SP, Brazil. Electronic address: caparada@unicamp.br.
authors: Carlos Amilcar
authors: CA
authors: Parada
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000378:metabolism; D004177:Dipyrone / Q000008:administration & dosage*; D007278:Injections, Spinal; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015221:Potassium Channels; D043884:Receptor, Cannabinoid, CB1; C117780:mitochondrial K(ATP) channel; D004177:Dipyrone
keywords: 4-aminoantipyrine; 4-methylaminoantipyrine; Cannabinoid receptors; Dipyrone; Dipyrone (Metamizol) (PubChem CID: 23674183); K(ATP) channel; cGMP