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

D A Andersson, C Gentry, L Alenmyr, D Killander, Simon E Lewis, A Andersson, B Bucher, J L Galzi, O Sterner, S Bevan, E D Hogestatt, P M Zygmunt

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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, 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.
Original languageEnglish
Article number551
Pages (from-to)1-11
Number of pages11
JournalNature Communications
Volume2
DOIs
Publication statusPublished - 22 Nov 2011

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    Andersson, D. A., Gentry, C., Alenmyr, L., Killander, D., Lewis, S. E., Andersson, A., Bucher, B., Galzi, J. L., Sterner, O., Bevan, S., Hogestatt, E. D., & Zygmunt, P. M. (2011). TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol. Nature Communications, 2, 1-11. [551]. https://doi.org/10.1038/ncomms1559