The profile of FR140423, a novel anti-inflammatory compound, in yeast-induced rat hyperalgesia.
The mechanism of action of FR140423 (3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyra zole), a novel anti-inflammatory compound, in a rat yeast-induced hyperalgesic model was investigated and compared with those of indomethacin and morphine. We tested the inhibitory effects of FR140423 on the formation of arachidonic acid metabolites, prostaglandin (PG) E2, thromboxane (TX) B2 and leukotriene (LT) B4, in yeast-injected inflamed paws and the effect of the opioid receptor antagonist naloxone on FR140423-induced anti-hyperalgesic effect and inhibition of the formation of arachidonic acid metabolites. Oral administration of FR140423 showed a dose-dependent anti-hyperalgesic effect. This effect was fourfold more potent than that of indomethacin but less potent than that of morphine. Unlike morphine, FR140423 suppressed the levels of PGE2 and TXB2 but not LTB4 in inflamed paws. FR140423 did not inhibit yeast-induced paw edema. The anti-hyperalgesic effect of FR140423 in yeast-injected rat paws was partially blocked by naloxone. However, the inhibitory effects of FR140423 on the formation of PGE2 and TXB2 in yeast-injected rat paws were not antagonized by naloxone. These results suggest that FR140423 shows a potent anti-hyperalgesic effect mediated by inhibition of PGs in inflamed tissue and by activation of opioid receptors.
Ochi
T
T
Department of Immunology and Inflammation, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Fujii
T
T
Motoyama
Y
Y
Goto
T
T
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D007279:Injections, Subcutaneous; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011720:Pyrazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012441:Saccharomyces cerevisiae; D013454:Sulfoxides
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009292:Narcotic Antagonists; D011720:Pyrazoles; D013454:Sulfoxides; C108904:3-(difluoromethyl)-1-(4-methoxyphenyl)-5-(4-(methylsulfinyl)phenyl)pyrazole; D016718:Arachidonic Acid; D009270:Naloxone; D009020:Morphine; D007213:Indomethacin