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{"project":"2_test","denotations":[{"id":"24622769-9989926-95790175","span":{"begin":316,"end":318},"obj":"9989926"},{"id":"24622769-23240907-95790176","span":{"begin":400,"end":402},"obj":"23240907"},{"id":"24622769-12244105-95790177","span":{"begin":568,"end":570},"obj":"12244105"},{"id":"24622769-18297109-95790178","span":{"begin":1052,"end":1054},"obj":"18297109"},{"id":"24622769-15184902-95790179","span":{"begin":1579,"end":1581},"obj":"15184902"},{"id":"24622769-12421642-95790180","span":{"begin":1733,"end":1735},"obj":"12421642"},{"id":"24622769-12581177-95790181","span":{"begin":1848,"end":1850},"obj":"12581177"},{"id":"24622769-17321048-95790182","span":{"begin":2085,"end":2087},"obj":"17321048"},{"id":"24622769-19839937-95790183","span":{"begin":2228,"end":2230},"obj":"19839937"},{"id":"24622769-22420940-95790184","span":{"begin":2367,"end":2369},"obj":"22420940"},{"id":"24622769-11464074-95790185","span":{"begin":2589,"end":2591},"obj":"11464074"},{"id":"24622769-1846934-95790186","span":{"begin":2684,"end":2686},"obj":"1846934"},{"id":"24622769-10698143-95790187","span":{"begin":2772,"end":2774},"obj":"10698143"},{"id":"24622769-18782385-95790188","span":{"begin":2947,"end":2949},"obj":"18782385"}],"text":"Non-steroidal anti-inflammatory agents (NSAIDs)\nNSAIDs inhibit two cyclooxygenase (COX) enzymes, COX1 and COX2, and thereby block the conversion of arachidonic acid (AA) into inflammatory prostaglandins. Ibuprofen, ketorolac, and flurbiprofen also block the hydrolysis of AEA into arachidonic acid and ethanolamine [27]. See Figure 2. A binding site for some NSAIDs on FAAH has also been identified [28]. NSAID inhibition of COX2 blocks the metabolism of AEA and 2-AG into prostaglandin ethanolamides (PG-EAs) and prostaglandin glycerol esters (PG-GEs), respectively [29]. PG-EAs and PG-GEs increase the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in primary cultured mouse hippocampal neurons, an effect opposite to that of their parent molecules [30].\n10.1371/journal.pone.0089566.g002 Figure 2 Anandamide (top figure) is metabolized into arachidonic acid and ethanolamine (bottom figures). Prostaglandin E2 glycerol ester (PGE2-GE), a COX2 metabolite of 2-AG, induced mechanical allodynia and thermal hyperalgesia in rat paws [31]. PGF2α-EA, a COX2 metabolite of AEA, was found in the spinal cord of mice with carrageenan-induced knee inflammation. PGF2α-EA contributed to pain perception and dorsal horn nociceptive neuron hyperactivity, thus providing a rationale for the combined use of COX2 and FAAH1 inhibitors against inflammatory pain [32].\nElectrophysiology studies of rat hippocampal cells showed that meloxicam and nimesulide prolonged and increased DSI; that is to say, the COX2 inhibitors potentiated synaptic 2-AG release and CB1 signaling [33]. Consistent with this, intrathecally applied indomethacin enhanced eCB-mediated antinociception in mice that was blocked by the CB1 antagonist AM251 [34]. Intrathecally applied flurbiprofen produced a similar eCB-dependent antinociception in the rat formalin test [35].\nCombining NSAIDs with cannabinoids (either eCBs or exogenous cannabinoids) produces additive or synergistic effects. A sub-effective dose of WIN55,212-2 became fully antinociceptive following administration of indomethacin in rats [36]. A local injection of ibuprofen plus AEA in the rat formalin test produced synergistic antinociceptive effects involving both CB1 and CB2 [37]. The FAAH inhibitor URB937, when coadministered to mice with indomethacin, produced a synergistic reduction in pain-related behaviors [38]. Furthermore, URB937 reduced the number and severity of gastric lesions produced by indomethacin. One contrary study showed that THC's decrease in intraocular pressure was partially blocked by indomethacin in rabbits [39].\nIn a small human study, the administration of indomethacin antagonized marijuana effects [40]. Yet a high dose of ibuprofen may cause sedation, possibly a cannabimimetic effect [41]. Clinical anecdotes of NSAIDs eliciting cannabimimetic effects have been reported; the individuals are usually familiar with the effects of cannabis, and usually females [42].\nIn summary, preclinical studies indicate that some NSAIDs inhibit FAAH and enhance the activity of eCBs, phytocannabinoids, and synthetic cannabinoids. Combinational effects may be particularly relevant at peripheral sites, such as the peripheral terminals of nociceptors."}

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