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 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.

Investigation of Diacylglycerol Lipase Alpha Inhibition in the Mouse Lipopolysaccharide Inflammatory Pain Model

“…In particular, KT109 as well as DAGL-b deletion resulted in decreased levels of a variety of proinflammatory lipids and proteins in LPS-stimulated peritoneal macrophage (Hsu et al, 2012). Specifically, prostaglandins are crucial for the development and maintenance of inflammatory pain (Ulmann et al, 2010;Endo et al, 2014;Sugita et al, 2016). DAGL-b inhibition is also protective from microglial activation in the brains of mice repeatedly administered LPS (Viader et al, 2016) and specifically produces reversal of LPS-stimulated proinflammatory cytokine release (Hsu et al, 2012) as well as reverses allodynia and thermal sensitivity in inflammatory, chronic constriction injury of the sciatic nerve, and chemotherapy-induced peripheral neuropathy pain models (Wilkerson et al, 2016).…”

The Prostaglandin EP3 Receptor Is an Independent Negative Prognostic Factor for Cervical Cancer Patients

“…The receptors are G protein-coupled receptors with seven transmembrane domains [ 6 ]. The prostaglandins play an important role in the induction of fever, pain, infection, immunity, and the stimulation of the hypothalamic-pituitary-adrenal axis [ 7 ]. Some of the prostaglandins are implicated in many aspects of reproductive functions.…”

L161982 alleviates collagen-induced arthritis in mice by increasing Treg cells and down-regulating Interleukin-17 and monocyte-chemoattractant protein-1 levels

“…PGE2 receptor antagonists have been studied in many fields, including tumor and some pain treatments, and have the potential to suppress tumor-associated lymph angiogenesis and, consequently, lymphatic metastasis in breast cancer [ 21 , 22 ]. Furthermore, co-administration of EP4 antagonists CJ-023423 and RO3244019 also showed an analgesic effect in a rat model [ 23 ]. This also indicated that EP4 antagonists may be therapeutically useful for RA, but the specific EP4 receptor antagonist L161982 still lacks evidence.…”