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The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1–mediated hypothermia and is associated with prostaglandin inhibition in the brain

Mirrasekhian, Elahe; Nilsson, Johan L.A. LU ; Shionoya, Kiseko; Blomgren, Anders LU ; Zygmunt, Peter M. LU ; Engblom, David; Högestätt, Edward D. LU and Blomqvist, Anders (2018) In FASEB Journal 32(10). p.5751-5759
Abstract

The mode of action of paracetamol (acetaminophen), which is widely used for treating pain and fever, has remained obscure, but may involve several distinct mechanisms, including cyclooxygenase inhibition and transient receptor potential ankyrin 1 (TRPA1) channel activation, the latter being recently associated with paracetamol’s propensity to elicit hypothermia at higher doses. Here, we examined whether the antipyretic effect of paracetamol was due to TRPA1 activation or cyclooxygenase inhibition. Treatment of wild-type and TRPA1 knockout mice rendered febrile by immune challenge with LPS with a dose of paracetamol that did not produce hypothermia (150 mg/kg) but is known to be analgetic, abolished fever in both genotypes. Paracetamol... (More)

The mode of action of paracetamol (acetaminophen), which is widely used for treating pain and fever, has remained obscure, but may involve several distinct mechanisms, including cyclooxygenase inhibition and transient receptor potential ankyrin 1 (TRPA1) channel activation, the latter being recently associated with paracetamol’s propensity to elicit hypothermia at higher doses. Here, we examined whether the antipyretic effect of paracetamol was due to TRPA1 activation or cyclooxygenase inhibition. Treatment of wild-type and TRPA1 knockout mice rendered febrile by immune challenge with LPS with a dose of paracetamol that did not produce hypothermia (150 mg/kg) but is known to be analgetic, abolished fever in both genotypes. Paracetamol completely suppressed the LPS-induced elevation of prostaglandin E2 in the brain and also reduced the levels of several other prostanoids. The hypothermia induced by paracetamol was abolished in mice treated with the electrophile-scavenger N-acetyl cysteine. We conclude that paracetamol’s antipyretic effect in mice is dependent on inhibition of cyclooxygenase activity, including the formation of pyrogenic prostaglandin E2, whereas paracetamol-induced hypothermia likely is mediated by the activation of TRPA1 by electrophilic metabolites of paracetamol, similar to its analgesic effect in some experimental paradigms.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Acetaminophen, Fever, N-acetyl cysteine, NAPQI, TRPA1
in
FASEB Journal
volume
32
issue
10
pages
9 pages
publisher
The Federation of American Societies for Experimental Biology
external identifiers
  • scopus:85054076267
ISSN
0892-6638
DOI
10.1096/fj.201800272R
language
English
LU publication?
yes
id
cec712ae-4088-4df8-b88c-440ed5305f46
date added to LUP
2018-10-09 13:01:46
date last changed
2019-02-20 11:30:32
@article{cec712ae-4088-4df8-b88c-440ed5305f46,
  abstract     = {<p>The mode of action of paracetamol (acetaminophen), which is widely used for treating pain and fever, has remained obscure, but may involve several distinct mechanisms, including cyclooxygenase inhibition and transient receptor potential ankyrin 1 (TRPA1) channel activation, the latter being recently associated with paracetamol’s propensity to elicit hypothermia at higher doses. Here, we examined whether the antipyretic effect of paracetamol was due to TRPA1 activation or cyclooxygenase inhibition. Treatment of wild-type and TRPA1 knockout mice rendered febrile by immune challenge with LPS with a dose of paracetamol that did not produce hypothermia (150 mg/kg) but is known to be analgetic, abolished fever in both genotypes. Paracetamol completely suppressed the LPS-induced elevation of prostaglandin E<sub>2</sub> in the brain and also reduced the levels of several other prostanoids. The hypothermia induced by paracetamol was abolished in mice treated with the electrophile-scavenger N-acetyl cysteine. We conclude that paracetamol’s antipyretic effect in mice is dependent on inhibition of cyclooxygenase activity, including the formation of pyrogenic prostaglandin E<sub>2</sub>, whereas paracetamol-induced hypothermia likely is mediated by the activation of TRPA1 by electrophilic metabolites of paracetamol, similar to its analgesic effect in some experimental paradigms.</p>},
  author       = {Mirrasekhian, Elahe and Nilsson, Johan L.A. and Shionoya, Kiseko and Blomgren, Anders and Zygmunt, Peter M. and Engblom, David and Högestätt, Edward D. and Blomqvist, Anders},
  issn         = {0892-6638},
  keyword      = {Acetaminophen,Fever,N-acetyl cysteine,NAPQI,TRPA1},
  language     = {eng},
  number       = {10},
  pages        = {5751--5759},
  publisher    = {The Federation of American Societies for Experimental Biology},
  series       = {FASEB Journal},
  title        = {The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1–mediated hypothermia and is associated with prostaglandin inhibition in the brain},
  url          = {http://dx.doi.org/10.1096/fj.201800272R},
  volume       = {32},
  year         = {2018},
}