title: Simultaneous Inhibition of PGE2 and PGI2 Signals 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 PGE2 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 PGE2 selectively, 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 PGI2 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 PGE2 receptor 4 (EP4) antagonist, CJ-023423, and RO3244019 also showed an analgesic effect. These findings suggest that both PGE2 signaling, especially through the EP4 receptor, and PGI2 signaling play critical roles in inflammatory pain and concurrent inhibition of both signals is important for suppression of inflammatory hyperalgesia.
authors.affiliation: Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Ryusuke
authors.identifier: 0000-0002-6905-2808
authors.initials: R
authors.lastname: Sugita
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Kuwabara
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Kazufumi
authors.identifier: 0000-0003-3278-9520
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Kotaro
authors.identifier: 0000-0002-3659-3456
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Toshihiro
authors.identifier: 0000-0003-1321-9581
authors.initials: T
authors.lastname: Kiho
authors.affiliation: Venture Science Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Atsushi
authors.identifier: 0000-0003-1773-7255
authors.initials: A
authors.lastname: Tengeiji
authors.affiliation: Global Project Management Department, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Katsuhiro
authors.identifier: 0000-0003-0000-3159
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Kohei
authors.identifier: 0000-0002-9806-973X
authors.initials: K
authors.lastname: Shimada
mesh_terms: D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy; D008264:Macrophages / Q000187:drug effects; D008297:Male; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000627:therapeutic use; D007093:Imidazoles; D011725:Pyridines; D013453:Sulfonylurea Compounds; D000096926:Benzenesulfonamides
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone; D011464:Epoprostenol; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; C522837:grapiprant; D007093:Imidazoles; D011725:Pyridines; D013453:Sulfonylurea Compounds; D000096926:Benzenesulfonamides