PMC:3951193 / 16129-17888 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3951193","sourcedb":"PMC","sourceid":"3951193","source_url":"http://www.ncbi.nlm.nih.gov/pmc/3951193","text":"Acetaminophen\nAcetaminophen (paracetamol), following deacetylation to its metabolite p-aminophenol, is conjugated with AA to form N-arachidonoylphenolamine (NAP, aka AM404). It is likely that deacetylation takes place mainly in the liver, and conjugation occurs in the central nervous system. NAP blocks the breakdown of AEA by FAAH, inhibits COX1 and COX2, and acts as a TRPV1 agonist [43]. The analgesic activity of acetaminophen in rats is blocked by CB1 or CB2 antagonists [44], [45]. Analgesic activity is also lost in CB1 −/− knockout mice [46]. A sub-effective dose of the synthetic cannabinoid WIN55,212-2 became effective following intracisternal administration of acetaminophen in rats [36]. A sub-effective dose of AEA in mice became anxiolytic in the Vogel conflict test and the social interaction test when co-administered with acetaminophen; the effect was blocked by the CB1 antagonist AM251 [47].\nSmall amounts of acetaminophen are also metabolized via the cytochrome P-450 pathway into N-acetyl-p-benzoquinone imine (NAPQI). Intrathecal administration of NAPQI activates TRPA1 and imparts antinociception in the mouse hot-plate test, and a similar action is found for Δ9-tetrahydrocannabiorcol. These effects are lost in Trpa1(−/−) mice [48].\nIn summary, preclinical studies indicate that acetaminophen enhances the activity of eCBs and synthetic cannabinoids in rodents. Why acetaminophen fails to elicit cannabimimetic effects in humans is unknown. Acetaminophen-cannabinoid drug interactions may be species-specific; Gould et al. [49] demonstrated strain-specific differences in mice. They suggested that other indirect actions of acetaminophen, including 5-HT receptor agonism, may outweigh any CB1 mediated effects in some mouse 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