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

DA Andersson, C Gentry, L Alenmyr, D Killander… - Nature …, 2011 - nature.com
DA Andersson, C Gentry, L Alenmyr, D Killander, SE Lewis, A Andersson, B Bucher, JL Galzi
Nature communications, 2011nature.com
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 …
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.
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