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

Summary, in 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.

• 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
• Department/s: Division of Clinical Chemistry and Pharmacology; Centre for Analysis and Synthesis
• Publishing year: 2011
• Language: English
• Publication/Series: Nature Communications
• Volume: 2
• Links: http://dx.doi.org/10.1038/ncomms1559
• Document type: Journal article
• Publisher: Nature Publishing Group
• Topic: Medicinal Chemistry; Pharmacology and Toxicology
• Status: Published
• ISBN/ISSN/Other: ISSN: 2041-1723