TRPV1 in Brain Is Involved in Acetaminophen-Induced Antinociception
Mallet, Christophe ; Barriere, David A. ; Ermund, Anna LU ; Jönsson, Bo A LU ; Eschalier, Alain ; Zygmunt, Peter LU
and Högestätt, Edward
LU
(2010)
In PLoS ONE
5(9).
- Abstract
- Background: Acetaminophen, the major active metabolite of acetanilide in man, has become one of the most popular overthe- counter analgesic and antipyretic agents, consumed by millions of people daily. However, its mechanism of action is still a matter of debate. We have previously shown that acetaminophen is further metabolized to N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404) by fatty acid amide hydrolase (FAAH) in the rat and mouse brain and that this metabolite is a potent activator of transient receptor potential vanilloid 1 (TRPV1) in vitro. Pharmacological activation of TRPV1 in the midbrain periaqueductal gray elicits antinociception in rats. It is therefore possible that activation of TRPV1 in the brain contributes... (More)
- Background: Acetaminophen, the major active metabolite of acetanilide in man, has become one of the most popular overthe- counter analgesic and antipyretic agents, consumed by millions of people daily. However, its mechanism of action is still a matter of debate. We have previously shown that acetaminophen is further metabolized to N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404) by fatty acid amide hydrolase (FAAH) in the rat and mouse brain and that this metabolite is a potent activator of transient receptor potential vanilloid 1 (TRPV1) in vitro. Pharmacological activation of TRPV1 in the midbrain periaqueductal gray elicits antinociception in rats. It is therefore possible that activation of TRPV1 in the brain contributes to the analgesic effect of acetaminophen. Methodology/Principal Findings: Here we show that the antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity is absent in FAAH and TRPV1 knockout mice in the formalin, tail immersion and von Frey tests. This dose of acetaminophen did not affect the global brain contents of prostaglandin E-2 (PGE(2)) and endocannabinoids. Intracerebroventricular injection of AM404 produced a TRPV1-mediated antinociceptive effect in the mouse formalin test. Pharmacological inhibition of TRPV1 in the brain by intracerebroventricular capsazepine injection abolished the antinociceptive effect of oral acetaminophen in the same test. Conclusions: This study shows that TRPV1 in brain is involved in the antinociceptive action of acetaminophen and provides a strategy for developing central nervous system active oral analgesics based on the coexpression of FAAH and TRPV1 in the brain. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1695798
- author
- Mallet, Christophe
; Barriere, David A.
; Ermund, Anna
LU
; Jönsson, Bo A
LU
; Eschalier, Alain
; Zygmunt, Peter
LU
and Högestätt, Edward
LU
- organization
- publishing date
- 2010
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS ONE
- volume
- 5
- issue
- 9
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- wos:000281960800008
- scopus:77958557341
- pmid:20862299
- ISSN
- 1932-6203
- DOI
- 10.1371/journal.pone.0012748
- language
- English
- LU publication?
- yes
- id
- fb536f25-f828-4ed3-a766-4f186c9a4ddf (old id 1695798)
- date added to LUP
- 2016-04-01 12:52:44
- date last changed
- 2022-05-07 06:10:28
@article{fb536f25-f828-4ed3-a766-4f186c9a4ddf,
abstract = {{Background: Acetaminophen, the major active metabolite of acetanilide in man, has become one of the most popular overthe- counter analgesic and antipyretic agents, consumed by millions of people daily. However, its mechanism of action is still a matter of debate. We have previously shown that acetaminophen is further metabolized to N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404) by fatty acid amide hydrolase (FAAH) in the rat and mouse brain and that this metabolite is a potent activator of transient receptor potential vanilloid 1 (TRPV1) in vitro. Pharmacological activation of TRPV1 in the midbrain periaqueductal gray elicits antinociception in rats. It is therefore possible that activation of TRPV1 in the brain contributes to the analgesic effect of acetaminophen. Methodology/Principal Findings: Here we show that the antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity is absent in FAAH and TRPV1 knockout mice in the formalin, tail immersion and von Frey tests. This dose of acetaminophen did not affect the global brain contents of prostaglandin E-2 (PGE(2)) and endocannabinoids. Intracerebroventricular injection of AM404 produced a TRPV1-mediated antinociceptive effect in the mouse formalin test. Pharmacological inhibition of TRPV1 in the brain by intracerebroventricular capsazepine injection abolished the antinociceptive effect of oral acetaminophen in the same test. Conclusions: This study shows that TRPV1 in brain is involved in the antinociceptive action of acetaminophen and provides a strategy for developing central nervous system active oral analgesics based on the coexpression of FAAH and TRPV1 in the brain.}},
author = {{Mallet, Christophe and Barriere, David A. and Ermund, Anna and Jönsson, Bo A and Eschalier, Alain and Zygmunt, Peter and Högestätt, Edward}},
issn = {{1932-6203}},
language = {{eng}},
number = {{9}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS ONE}},
title = {{TRPV1 in Brain Is Involved in Acetaminophen-Induced Antinociception}},
url = {{http://dx.doi.org/10.1371/journal.pone.0012748}},
doi = {{10.1371/journal.pone.0012748}},
volume = {{5}},
year = {{2010}},
}