Recent research showed the involvement of
prostaglandin E receptor subtype 4 (EP4) in
hypersensitivity to inflammatory
pain and suggested that the EP4 receptor is a potential target for the pharmacological treatment of inflammatory
pain. We examined the effects of
(S)-4-(1-(5-chloro-2-(4-fluorophenyoxy) benzamido)ethyl) benzoic acid (CJ-42794), a selective EP4 antagonist, on gastrointestinal ulcerogenic and healing responses in rats, in comparison with those of various
cyclooxygenase (COX) inhibitors.
CJ-42794 alone, given p.o., did not produce any damage in the gastrointestinal mucosa, similar to 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560) (COX-1 inhibitor) or
rofecoxib (COX-2 inhibitor), whereas
indomethacin (nonselective COX inhibitor) caused gross lesions.
Rofecoxib but not
CJ-42794, however, damaged these tissues when coadministered with
SC-560 and aggravated gastric lesions produced by
aspirin.
Indomethacin and
SC-560 worsened the gastric ulcerogenic response to cold-restraint stress, yet neither
CJ-42794 nor
rofecoxib had any effect. Furthermore,
indomethacin and
SC-560 at lower doses damaged the stomach and small intestine of adjuvant arthritic rats. In arthritic rats,
rofecoxib but not
CJ-42794 provoked gastric ulceration, whereas
CJ-42794 produced little damage in the small intestine. The repeated administration of
CJ-42794 and
rofecoxib as well as
indomethacin impaired the healing of chronic
gastric ulcers with a down-regulation of
vascular endothelial growth factor expression in the ulcerated mucosa. These results suggest that
CJ-42794 does not cause any damage in the normal rat gastrointestinal mucosa and in the arthritic rat stomach and does not worsen the gastric ulcerogenic response to stress or
aspirin in normal rats, although this agent slightly damages the small intestine of arthritic rats and impairs the healing of
gastric ulcers.