Abstract
BackgroundAcetaminophen, 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 (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 FindingsHere 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 E2 (PGE2) 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.ConclusionsThis 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.
Highlights
In 1948, Brodie and Axelrod demonstrated that acetaminophen is the major active metabolite of acetanilide in man [1]
This study shows that transient receptor potential vanilloid 1 (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 fatty acid amide hydrolase (FAAH) and TRPV1 in the brain
We have recently shown that acetaminophen is metabolized by FAAH to the Nacylphenolamine AM404 in the rodent nervous system and that inhibitors of FAAH prevent the antinociceptive effect of acetaminophen in rat [6,12]
Summary
In 1948, Brodie and Axelrod demonstrated that acetaminophen is the major active metabolite of acetanilide in man [1]. We have recently shown that acetaminophen is metabolized by FAAH to the Nacylphenolamine AM404 in the rodent nervous system and that inhibitors of FAAH prevent the antinociceptive effect of acetaminophen in rat [6,12] This compound, which possesses analgesic activity in models of nociceptive and neuropathic pain [13,14,15,16,17,18,19,20], was originally proposed to be an inhibitor of cellular uptake and degradation of anandamide [21]. 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. It is possible that activation of TRPV1 in the brain contributes to the analgesic effect of acetaminophen
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