Takehiro Ochi, Takashi Fujii, Yukio Motoyama and Toshio Goto
Department of Immunology and Inflammation, Medicinal Biology Research
Laboratories, Fujisawa Pharmaceutical Co., Ltd., 1 - 6, Kashima 2-chome,
Yodogawa-ku, Osaka 532 - 8514, Japan
Abstract: The mechanism of action of FR140423 (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 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.
Keywords: FR140423, Yeast-induced hyperalgesia, Prostaglandin formation,
Opioid