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

      brief-report

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          Abstract

          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.

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          Most cited references12

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          TRPA1 underlies a sensing mechanism for O2.

          Oxygen (O(2)) is a prerequisite for cellular respiration in aerobic organisms but also elicits toxicity. To understand how animals cope with the ambivalent physiological nature of O(2), it is critical to elucidate the molecular mechanisms responsible for O(2) sensing. Here our systematic evaluation of transient receptor potential (TRP) cation channels using reactive disulfides with different redox potentials reveals the capability of TRPA1 to sense O(2). O(2) sensing is based upon disparate processes: whereas prolyl hydroxylases (PHDs) exert O(2)-dependent inhibition on TRPA1 activity in normoxia, direct O(2) action overrides the inhibition via the prominent sensitivity of TRPA1 to cysteine-mediated oxidation in hyperoxia. Unexpectedly, TRPA1 is activated through relief from the same PHD-mediated inhibition in hypoxia. In mice, disruption of the Trpa1 gene abolishes hyperoxia- and hypoxia-induced cationic currents in vagal and sensory neurons and thereby impedes enhancement of in vivo vagal discharges induced by hyperoxia and hypoxia. The results suggest a new O(2)-sensing mechanism mediated by TRPA1.
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            TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ(9)-tetrahydrocannabiorcol.

            TRPA1 is a unique sensor of noxious stimuli and, hence, a potential drug target for analgesics. Here we show that the antinociceptive effects of spinal and systemic administration of acetaminophen (paracetamol) are lost in Trpa1(-/-) mice. The electrophilic metabolites N-acetyl-p-benzoquinoneimine and p-benzoquinone, but not acetaminophen itself, activate mouse and human TRPA1. These metabolites also activate native TRPA1 and, as a consequence, reduce voltage-gated calcium and sodium currents in primary sensory neurons. The N-acetyl-p-benzoquinoneimine metabolite L-cysteinyl-S-acetaminophen was detected in the mouse spinal cord after systemic acetaminophen administration. In the hot-plate test, intrathecal administration of N-acetyl-p-benzoquinoneimine, p-benzoquinone and the electrophilic TRPA1 activator cinnamaldehyde produced antinociception that was lost in Trpa1(-/-) mice. Intrathecal injection of a non-electrophilic cannabinoid, Δ(9)-tetrahydrocannabiorcol, also produced TRPA1-dependent antinociception in this test. Our study provides a molecular mechanism for the antinociceptive effect of acetaminophen and discloses spinal TRPA1 activation as a potential pharmacological strategy to alleviate pain.
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              Oxidative challenges sensitize the capsaicin receptor by covalent cysteine modification.

              The capsaicin receptor TRPV1, one of the major transduction channels in the pain pathway, integrates information from extracellular milieu to control excitability of primary nociceptive neurons. Sensitization of TRPV1 heightens pain sensation to moderately noxious or even innocuous stimuli. We report here that oxidative stress markedly sensitizes TRPV1 in multiple species' orthologs. The sensitization can be recapitulated in excised inside-out membrane patches, reversed by strong reducing agents, and blocked by pretreatment with maleimide that alkylates cysteines. We identify multiple cysteines required for full modulation of TRPV1 by oxidative challenges. Robust oxidative modulation recovers the agonist sensitivity of receptors desensitized by prolonged exposure to capsaicin. Moreover, oxidative modulation operates synergistically with kinase or proton modulations. Thus, oxidative modulation is a robust mechanism tuning TRPV1 activity via covalent modification of evolutionarily conserved cysteines and may play a role in pain sensing processes during inflammation, infection, or tissue injury.
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                Author and article information

                Journal
                Pain Rep
                Pain Rep
                PAIREP
                Painreports
                Pain Reports
                Wolters Kluwer (Philadelphia, PA )
                2471-2531
                May-Jun 2019
                09 April 2019
                : 4
                : 3
                : e720
                Affiliations
                Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
                Author notes
                [* ]Corresponding author. Address: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Tel.: +49‐5115323484. E-mail address: leffler.andreas@ 123456mh-hannover.de (A. Leffler).
                Article
                PAINREPORTS-D-18-0070 00011
                10.1097/PR9.0000000000000720
                6749899
                31583344
                fca7e07b-040f-4437-813d-ad3ce96acb4d
                Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

                This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 August 2018
                : 08 January 2019
                : 17 January 2019
                Categories
                10
                Pharmacology
                Brief Report
                Custom metadata
                TRUE

                dipyrone,metamizol,analgesia,trpv1,trpa1
                dipyrone, metamizol, analgesia, trpv1, trpa1

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