TRPV1 in Brain Is Involved in Acetaminophen-Induced Antinociception
TRPV1 in Brain Is Involved in Acetaminophen-Induced Antinociception
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DOI：
10.1371/journal.pone.0012748
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发表时间：
2010-09-17
期刊：
影响因子：
3.7
通讯作者：
Hogestatt, Edward D.
中科院分区：
文献类型：
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作者：
Mallet, Christophe;Barriere, David A.;Hogestatt, Edward D.
背景：对乙酰氨基酚是人体乙酰苯胺的主要活性代谢物，已成为最流行的非处方镇痛解热剂之一，每天有数百万人服用。然而，其作用机制仍存在争议。我们之前已经证明，对乙酰氨基酚在大鼠和小鼠大脑中被脂肪酸酰胺水解酶 (FAAH) 进一步代谢为 N-(4-羟苯基)-5Z,8Z,11Z,14Z-二十碳四烯酰胺 (AM404)，并且该代谢物在体外是瞬时受体电位香草酸 1 (TRPV1) 的有效激活剂。中脑导水管周围灰质中 TRPV1 的药理学激活可引起大鼠的镇痛作用。因此，大脑中 TRPV1 的激活可能有助于对乙酰氨基酚的镇痛作用。 方法/主要发现：在这里，我们表明，在福尔马林、尾部浸没和 von Frey 试验中，FAAH 和 TRPV1 敲除小鼠中缺乏运动功能减退的口服剂量的对乙酰氨基酚不具有镇痛作用。该剂量的对乙酰氨基酚不影响前列腺素 E-2 (PGE(2)) 和内源性大麻素的全脑含量。在小鼠福尔马林试验中，脑室内注射 AM404 产生 TRPV1 介导的镇痛作用。脑室内注射辣椒西平对脑内TRPV1的药理抑制作用消除了口服对乙酰氨基酚的镇痛作用。结论：本研究表明脑内TRPV1参与对乙酰氨基酚的镇痛作用，并为开发基于脑内FAAH和TRPV1共表达的中枢神经系统活性口服镇痛药提供了策略。
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.