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 (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 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. 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. [ABSTRACT FROM AUTHOR]