Prostacyclin Antagonism Reduces Pain and Inflammation in Rodent Models of Hyperalgesia and Chronic Arthritis

Abstract

The inhibition of prostaglandin (PG) synthesis is at the center of current anti-inflammatory therapies. Because cyclooxygenase-2 (COX-2) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of multiple PGs, there is currently a strong focus on characterizing the role of the different PGs in the inflammation process and development of arthritis. Evidence to date suggests that both PGE 2 and PGI 2 act as mediators of pain and inflammation. Most of the data indicating a role for PGI 2 in this context have been generated in animal models of acute pain. Herein, we describe the role of PGI 2 in models of osteoarthritis (OA) and rheumatoid arthritis using a highly selective PGI 2 receptor (IP, Ptgir) antagonist and IP receptor-deficient mice. In the rat OA model using monoiodoacetate injection into the knee joint, the IP antagonist reduced pain with an efficacy approaching that of the NSAID diclofenac. In a chronic model of inflammatory arthritis, collagen-antibody induced arthritis model in mice, IP receptordeficient mice displayed a 91% reduction in arthritis score. Interestingly, pretreatment with the IP [N-[4-(imidazolidin-2-ylideneamino)-benzyl]-4-methoxy-benzamide] antagonist in this model also caused a significant reduction of the symptoms, whereas administration of the compound after the initiation of arthritis had no detectable effect. Our data indicate that, in addition to its role in acute inflammation, PGI 2 is involved in the development of chronic inflammation. The results also suggest that the inhibition of PGI 2 synthesis by NSAIDs and COX-2 inhibitors, in addition to that of PGE 2 , contributes to their efficacy in treating the signs of arthritis.

Prostaglandin I 2 upregulates the expression of anterior pharynx‐defective‐1α and anterior pharynx‐defective‐1β in amyloid precursor protein/presenilin 1 transgenic mice

“…Because evidence suggests that PGI 2 is a potential mediator of neuroinflammation (Ford‐Hutchinson et al ., 1978; Honda et al ., 2005; Pulichino et al ., 2006), we sought to determine the concentration of PGI 2 in APP/PS1 transgenic mice at 6 months of age. As shown in Fig.…”

Mutual antagonistic relationship between prostaglandin E2 and IFN‐γ: Implications for rheumatoid arthritis

“…Using LC-MS, we measured the effect of IFN-c on the release of PGE 2 in whole blood and FLS. We also assessed the effects of IFN-c on PGI 2 , another prostaglandin thought to have an important role in RA [26,27]. As shown in Fig.…”

Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

“…PGI 2 is a mediator of edema and pain in both acute and chronic inflammation (Pulichino et al, 2006). Bradykinin induces PGI 2 formation and enhances microvascular permeability and edema (Hata and Breyer, 2004).…”