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J. Biol. Chem., Vol. 279, Issue 23, 24866-24872, June 4, 2004

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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^*

Jocelyne Guay, Kevin Bateman, Robert Gordon¶, Joseph Mancini, and Denis Riendeau||

From the Departments of Biochemistry and Molecular Biology, Medicinal Chemistry and ^¶Pharmacology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec H9H 3L1, Canada

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 PGE₂ and thromboxane (TX)B₂ levels and with a peak of COX-2 expression that preceded that of microsomal prostaglandin-E₂ synthase-1 (mPGES-1). COX-2 and mPGES-1 remained elevated during the late phase, and PGE₂ continued to further increase through 24 h. The cytosolic PGE₂ 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 PGE₂, 6-keto-PGF₁, PGD₂, and TXB₂ were detected during the early phase. PGE₂ 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 PGD₂, 6-keto-PGF₁, and TXB₂ in addition to the major PGE₂ response. The data also indicate that the up-regulation of mPGES-1 contributes to COX-2-mediated PGE₂ production in the CNS during peripheral inflammation.

Received for publication, March 19, 2004

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 514-428-2673; Fax: 514-428-4930; E-mail: denis_riendeau{at}merck.com.

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