TRPV1 in brain is involved in acetaminophen-induced antinociception.
BACKGROUND
Acetaminophen, the major active metabolite of acetanilide in man, has become one of the most popular over-the-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 (TRPV(1)) in vitro. Pharmacological activation of TRPV(1) in the midbrain periaqueductal gray elicits antinociception in rats. It is therefore possible that activation of TRPV(1) in the brain contributes to the analgesic effect of acetaminophen.


RESULTS
Here we show that the antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity is absent in FAAH and TRPV(1) 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 TRPV(1)-mediated antinociceptive effect in the mouse formalin test. Pharmacological inhibition of TRPV(1) in the brain by intracerebroventricular capsazepine injection abolished the antinociceptive effect of oral acetaminophen in the same test.


CONCLUSIONS
This study shows that TRPV(1) 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 TRPV(1) in the brain.
Mallet
Christophe
C
Clermont Université, Université d'Auvergne, Pharmacologie fondamentale et clinique de la douleur, Clermont-Ferrand, France.
Barrière
David A
DA
Ermund
Anna
A
Jönsson
Bo A G
BA
Eschalier
Alain
A
Zygmunt
Peter M
PM
Högestätt
Edward D
ED
D000082:Acetaminophen / Q000008:administration & dosage* / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000378:metabolism*
D018712:Analgesics, Non-Narcotic; D063385:Cannabinoid Receptor Modulators; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; D000082:Acetaminophen