Simultaneous Inhibition of PGE(2) and PGI(2) Signals Is Necessary to Suppress Hyperalgesia in Rat Inflammatory Pain Models

Prostaglandin E(2) (PGE(2)) is well known as a mediator of inflammatory symptoms such as fever, arthritis, and inflammatory pain. In the present study, we evaluated the analgesic effect of our selective PGE(2) synthesis inhibitor, compound I, 2-methyl-2-[cis-4-([1-(6-methyl-3-phenylquinolin-2-yl)piperidin-4-yl]carbonyl amino)cyclohexyl] propanoic acid, in rat yeast-induced acute and adjuvant-induced chronic inflammatory pain models. Although this compound suppressed the synthesis of PGE(2) selectively, no analgesic effect was shown in both inflammatory pain models. Prostacyclin (PGI(2)) also plays crucial roles in inflammatory pain, so we evaluated the involvement of PGI(2) signaling in rat inflammatory pain models using prostacyclin receptor (IP) antagonist, RO3244019. RO3244019 showed no analgesic effect in inflammatory pain models, but concomitant administration of compound I and RO3244019 showed analgesic effects comparable to celecoxib, a specific cyclooxygenase- (COX-) 2 inhibitor. Furthermore, coadministration of PGE(2) receptor 4 (EP4) antagonist, CJ-023423, and RO3244019 also showed an analgesic effect. These findings suggest that both PGE(2) signaling, especially through the EP4 receptor, and PGI(2) signaling play critical roles in inflammatory pain and concurrent inhibition of both signals is important for suppression of inflammatory hyperalgesia.