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 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

Further advances in the synthesis of endocannabinoid-related ligands

Recent advances in the synthesis of endocannabinoid-related ligands for the period 2001–2004 are covered in this review. During this period the first solid phase synthesis of anandamide (AEA) analogs was developed, which allows modification at both the head group and the end pentyl chain. Synthesis of water-soluble prodrugs of noladin, ether was reported, which are chemically stable, rapidly release noladin ether under enzymatic conditions and are shown to reduce intraocular pressure. The structure-activity relationships (SAR) of alkylcarbamic acid aryl esters and the discovery of potent, archidonylsulfonyl derivatives as fatty acid amide hydrolase (FAAH) inhibitors are summarized. Recent synthetic developments in the controversial area of anandamide membrane transporter (AMT) inhibitors are also discussed