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TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol

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  • David A Andersson

    (King's College London, Wolfson Centre for Age-Related Diseases,)

  • Clive Gentry

    (King's College London, Wolfson Centre for Age-Related Diseases,)

  • Lisa Alenmyr

    (Lund University, Skåne University Hospital)

  • Dan Killander

    (Centre for Analysis and Synthesis Organic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden.)

  • Simon E Lewis

    (1 South, University of Bath, Bath BA2 7AY, UK.)

  • Anders Andersson

    (Lund University, Skåne University Hospital)

  • Bernard Bucher

    (UMR 7213, CNRS/Université de Strasbourg, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, 74 route du Rhin, BP 60024, 67401 Illkirch, France.)

  • Jean-Luc Galzi

    (Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, UMR 7242, Ecole Supérieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant)

  • Olov Sterner

    (Centre for Analysis and Synthesis Organic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden.)

  • Stuart Bevan

    (King's College London, Wolfson Centre for Age-Related Diseases,)

  • Edward D Högestätt

    (Lund University, Skåne University Hospital
    Lund University Pain Research Centre, Lund University, SE-221 00)

  • Peter M Zygmunt

    (Lund University, Skåne University Hospital
    Lund University Pain Research Centre, Lund University, SE-221 00)

Abstract

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, Δ9-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.

Suggested Citation

  • David A Andersson & Clive Gentry & Lisa Alenmyr & Dan Killander & Simon E Lewis & Anders Andersson & Bernard Bucher & Jean-Luc Galzi & Olov Sterner & Stuart Bevan & Edward D Högestätt & Peter M Zygmun, 2011. "TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol," Nature Communications, Nature, vol. 2(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1559
    DOI: 10.1038/ncomms1559
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    Cited by:

    1. Liying Zhang & Charlotte Simonsen & Lucie Zimova & Kaituo Wang & Lavanya Moparthi & Rachelle Gaudet & Maria Ekoff & Gunnar Nilsson & Ute A. Hellmich & Viktorie Vlachova & Pontus Gourdon & Peter M. Zyg, 2022. "Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. A. Catalina Vélez-Ortega & Ruben Stepanyan & Stephanie E. Edelmann & Sara Torres-Gallego & Channy Park & Desislava A. Marinkova & Joshua S. Nowacki & Ghanshyam P. Sinha & Gregory I. Frolenkov, 2023. "TRPA1 activation in non-sensory supporting cells contributes to regulation of cochlear sensitivity after acoustic trauma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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