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TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Delta(9)-tetrahydrocannabiorcol

Author:
  • David A. Andersson
  • Clive Gentry
  • Lisa Alenmyr
  • Dan Killander
  • Simon E. Lewis
  • Anders S Andersson
  • Bernard Bucher
  • Jean-Luc Galzi
  • Olov Sterner
  • Stuart Bevan
  • Edward Högestätt
  • Peter Zygmunt
Publishing year: 2011
Language: English
Publication/Series: Nature Communications
Volume: 2
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

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, Delta(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.

Keywords

  • Medicinal Chemistry
  • Pharmacology and Toxicology

Other

Published
  • ISSN: 2041-1723
Olov Sterner
E-mail: olov.sterner [at] science.lu.se

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