Simultaneous Inhibition of PGE2and PGI2Signals Is Necessary to Suppress Hyperalgesia in Rat Inflammatory Pain Models

Abstract

Prostaglandin E2(PGE2) 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 PGE2synthesis 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 PGE2selectively, no analgesic effect was shown in both inflammatory pain models. Prostacyclin (PGI2) also plays crucial roles in inflammatory pain, so we evaluated the involvement of PGI2signaling 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 PGE2receptor 4 (EP4) antagonist, CJ-023423, and RO3244019 also showed an analgesic effect. These findings suggest that both PGE2signaling, especially through the EP4 receptor, and PGI2signaling play critical roles in inflammatory pain and concurrent inhibition of both signals is important for suppression of inflammatory hyperalgesia.