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

Andersson, David A. ; Gentry, Clive ; Alenmyr, Lisa LU ; Killander, Dan LU ; Lewis, Simon E. ; Andersson, Anders S LU ; Bucher, Bernard ; Galzi, Jean-Luc ; Sterner, Olov LU and Bevan, Stuart , et al. (2011) In Nature Communications 2.
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
2
article number
551
publisher
Nature Publishing Group
external identifiers
  • wos:000297686500038
  • scopus:82555196604
  • pmid:22109525
ISSN
2041-1723
DOI
10.1038/ncomms1559
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Division of Clinical Chemistry and Pharmacology (013250300), Organic chemistry (S/LTH) (011001240)
id
1c04a215-a674-4e38-993b-1d6f434bc9c7 (old id 2291675)
date added to LUP
2016-04-01 14:46:07
date last changed
2021-10-06 04:15:14
@article{1c04a215-a674-4e38-993b-1d6f434bc9c7,
  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.},
  author       = {Andersson, David A. and Gentry, Clive and Alenmyr, Lisa and Killander, Dan and Lewis, Simon E. and Andersson, Anders S and Bucher, Bernard and Galzi, Jean-Luc and Sterner, Olov and Bevan, Stuart and Högestätt, Edward and Zygmunt, Peter},
  issn         = {2041-1723},
  language     = {eng},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Delta(9)-tetrahydrocannabiorcol},
  url          = {http://dx.doi.org/10.1038/ncomms1559},
  doi          = {10.1038/ncomms1559},
  volume       = {2},
  year         = {2011},
}