Carrageenan-induced Paw Edema in Rat Elicits a Predominant Prostaglandin E2 (PGE2) Response in the Central Nervous System Associated with the Induction of Microsomal PGE2 Synthase-1

Abstract

Peripheral inflammation involves an increase in cyclooxygenase-2 (COX-2)-mediated prostaglandin (PG) synthesis in the central nervous system (CNS), which contributes to allodynia and hyperalgesia. In the present study we have determined the changes in prostanoid tissue levels and in expression of terminal prostanoid synthases in both the CNS and inflamed peripheral tissue during carrageenan-induced paw inflammation in the rat. Prostanoid levels were measured by liquid chromatography-mass spectrometry and enzyme expression at the RNA level by quantitative PCR analysis during both the early (1-6 h) and late (12 and 24 h) phases of the inflammatory response. In the paw, the early phase was associated with increases in PGE 2 and thromboxane (TX)B 2 levels and with a peak of COX-2 expression that preceded that of microsomal prostaglandin-E 2 synthase-1 (mPGES-1). COX-2 and mPGES-1 remained elevated during the late phase, and PGE 2 continued to further increase through 24 h. The cytosolic PGE 2 synthase (cPGES) showed a small transient increase during the early phase, whereas mPGES-2 expression was not affected by inflammation. In the cerebrospinal fluid, elevated levels of PGE 2 , 6-keto-PGF 1␣ , PGD 2 , and TXB 2 were detected during the early phase. PGE 2 levels also increased in the spinal cord and, to a lesser extent, in the brain and remained elevated in both the cerebrospinal fluid and the spinal cord during the late phase. The expression of mPGES-1 was strongly up-regulated in the brain and spinal cord during inflammation, whereas no change was detected for the expression of cPGES, mPGES-2, COX-1, and terminal PGD, TX, or PGI synthases. The results show that the carrageenan-induced edema in the paw elicits an early phase of COX-2 induction in the CNS leading to an increase synthesis in PGD 2 , 6-keto-PGF 1␣ , and TXB 2 in addition to the major PGE 2 response. The data also indicate that the up-regulation of mPGES-1 contributes to COX-2-mediated PGE 2 production in the CNS during peripheral inflammation.Carrageenan-induced inflammation in the rat paw represents a classical model of edema formation and hyperalgesia, which has been extensively used in the development of nonsteroidal anti-inflammatory drugs and selective COX 1 -2 inhibitors. Several lines of evidence indicate that the COX-2-mediated increase in prostaglandin (PG) E 2 production in the central nervous system (CNS) contributes to the severity of the inflammatory and pain responses in this model. COX-2 is rapidly induced in the spinal cord and other regions of the CNS following carrageenan injection in the paw (1). The administration of selective COX-2 inhibitors, but not COX-1 inhibitors, reduces the levels of PGE 2 in the cerebrospinal fluid (CSF) and hyperalgesia (2-5). In addition, it has been shown that the intrathecal administration of PGE 2 potentiates carrageenaninduced inflammation (6) and that the direct microinjection of PGE 2 in the brain causes hyperalgesia (7). Selective COX-2 inhibitors can also inhibit peripheral pain responses when g...

Inhibition of microsomal prostaglandin E2 synthase‐1 as a molecular basis for the anti‐inflammatory actions of boswellic acids from frankincense

“…However, PGE2 is a key mediator accounting for typical disease symptoms in OA and RA (Smith, 1989); and in patients suffering from RA or OA, a pivotal role for mPGES1 has been demonstrated (Westman et al, 2004;Li et al, 2005). Moreover, data from animal arthritis models support the relevance of mPGES1 to inflammatory joint diseases (Claveau et al, 2003;Trebino et al, 2003;Guay et al, 2004). Hence, the inhibition of PGE2 biosynthesis by b-BA may contribute to the beneficial effects of frankincense preparations observed in clinical studies and animal models of OA and RA (Ammon, 2006).…”

“…reduced the inflammatory reaction in two in vivo models of acute inflammation, carrageenan-induced mouse paw oedema and rat pleurisy, being about as effective as 5 mg·kg -1 indomethacin. During carrageenan-induced oedema formation, PGE2 levels are significantly elevated (Harada et al, 1982;Guay et al, 2004), and COX inhibitors prevent the inflammatory response (Gemmell et al, 1979). Results from studies using carrageenan-induced paw oedema and i.p.…”

“…Finally, we explored the efficacy of b-BA in carrageenan-induced paw oedema, another rodent model of acute inflammation, to assess the pathophysiological role of mPGES1 in inflammation in vivo (Guay et al, 2004). The injection of carrageenan into the mouse paw produced a marked increase of paw volume, with a maximal effect after 4 h. Pretreatment (30 min) of mice with b-BA attenuated the inflammatory response at 4 h ( Figure 7B).…”

Physiologic Advantages of Peripheral Nerve Blockade Translate to Decreased Length of Stay and Improved Patient Satisfaction

“…38 Throughout the entire experiment, COX1 levels were unchanged the entire time. [50][51][52][53] COX2 mRNA levels were increased in mice treated with carrageenan that did not receive nerve block. 50,52,53 The COX2 levels significantly increased throughout the spinal cord (both sides) but only increased on the side of injection at the dorsal root ganglion.…”

Fish oil and rheumatoid arthritis: past, present and future

“…AA is released from membrane phospholipids in response to inflammatory stimuli, whereupon the free AA is a substrate for COX and 5-lipoxygenase (5-LOX) with the production of PGE 2 and LTB 4 , respectively. PGE 2 synthesised peripherally by COX-1 and COX-2 results in swelling (27) , and PGE 2 produced in the central nervous system by constitutive/ inducible COX-2 and inducible PGE synthase results in hyperalgesia (28)(29)(30) . LTB 4 is a chemoattractant and activator of neutrophils, which are essential for inflammatory arthritis expression in animal models (31) and which are the most prominent leucocyte type in rheumatoid synovial fluid.…”