Active metabolites of dipyrone induce a redox-dependent activation of the ion channels TRPA1 and TRPV1.

Autor:	Schenk SA; Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany., Dick F; Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany., Herzog C; Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany., Eberhardt MJ; Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany., Leffler A; Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
Jazyk:	angličtina
Zdroj:	Pain reports [Pain Rep] 2019 Apr 09; Vol. 4 (3), pp. e720. Date of Electronic Publication: 2019 Apr 09 (Print Publication: 2019).
DOI:	10.1097/PR9.0000000000000720
Abstrakt:	Introduction: The nonopioid analgesic and antipyretic dipyrone (metamizol) is frequently used worldwide. Dipyrone is a prodrug, and the metabolites 4-N-methylaminoantipyrine (MAA) and 4-aminoantipyrine (AA) seem to induce analgesia and antipyresia in part by inhibiting cyclooxygenase. In mice, however, the analgesic effect of dipyrone also seems to depend on the ion channel TRPA1. In this study, we explored the effects of dipyrone and its active metabolites on recombinant and native TRPA1 and TRPV1 channels. Methods: Constructs human (h) TRPA1 and TRPV1 were expressed in HEK293 cells, and dorsal root ganglion neurons were isolated from adult mice. Effects of dipyrone, MAA, and AA were explored by means of whole-cell patch clamp recordings and ratiometric calcium imaging. Results: Dipyrone failed to activate both hTRPA1 and hTRPV1. However, both MAA and AA evoked small outwardly rectifying membrane currents and an increase of intracellular calcium in cells expressing hTRPA1 or hTRPV1. MAA also sensitized both channels and thus potentiated inward currents induced by carvacrol (hTRPA1) and protons (hTRPV1). MAA-induced activation was inhibited by the antioxidant 10-mM glutathione included in the pipette, and the mutant constructs hTRPA1-C621/C641/C665S and hTRPV1-C158A/C391S/C767S were insensitive to both MAA and AA. Mouse dorsal root ganglion neurons exhibited a marginal calcium influx when challenged with MAA. Conclusion: The metabolites MAA and AA, but not dipyrone itself, activate and sensitize the nociceptive ion channels TRPA1 and TRPV1 in a redox-dependent manner. These effects may be relevant for dipyrone-induced analgesia and antipyresia. Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)
Databáze:	MEDLINE
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