The profile of FR140423, a novel anti-inflammatory compound, in yeast-induced rat hyperalgesia

The mechanism of action of FR140323 (3-(difluoromethyl)-1-(4-methoxyphenyl) -5-[4-(methylsulfinyl)phenyl]pyrazole), a novel anti-inflammatory compound, in a rat yeast-induced hyperalgesic model was investigated and compared wi th those of indomethacin and morphine. We tested the inhibitory effects of FR140123 on the formation of arachidonic acid metabolites, prostaglandin (P G) E-2, thromboxane (TX) B-2 and leukotriene (LT) B-4, in yeast-injected in flamed paws and the effect of the opioid receptor antagonist naloxone on FR 140323-induced anti-hyperalgesic effect and inhibition of the formation of arachidonic acid metabolites. Oral administration of FR140323 showed a dose -dependent anti-hyperalgesic effect. This effect was fourfold more potent t han that of indomethacin but less potent than that of morphine. Unlike morp hine, FR140423 suppressed the levels of PGE(2) and TXB2 but not LTB4 in inf lamed paws. FR140423 did not inhibit yeast-induced paw edema. The anti-hype ralgesic effect of FR140523 in yeast-injected rat paws was partially blocke d by naloxone. However, the inhibitory effects of FR140123 on the formation of PGE(2) and TXB2 in yeast-injected rat paws were not antagonized by nalo xone. These results suggest that FR140423 shows a potent anti-hyperalgesic effect mediated by inhibition of PGs in inflamed tissue and by activation o f opioid receptors.