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Physiology and Pharmacology of Temperature Regulation

Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways?

¹Institut für Veterinär-Physiologie, Justus-Liebig-Universität Giessen, Giessen; and ²Institut für Ernährungsphysiologie, Bundesforschungsanstalt für Ernährung und Lebensmittel, Karlsruhe, Germany

Submitted 14 February 2005 ; accepted in final form 23 March 2005

In guinea pigs, dose-dependent febrile responses were induced by injection of a high (100 µg/kg) or a low (10 µg/kg) dose of bacterial lipopolysaccharide (LPS) into artificial subcutaneously implanted Teflon chambers. Both LPS doses further induced a pronounced formation of prostaglandin E₂ (PGE₂) at the site of localized subcutaneous inflammation. Administration of diclofenac, a nonselective cyclooxygenase (COX) inhibitor, at different doses (5, 50, 500, or 5,000 µg/kg) attenuated or abrogated LPS-induced fever and inhibited LPS-induced local PGE₂ formation (5 or 500 µg/kg diclofenac). Even the lowest dose of diclofenac (5 µg/kg) attenuated fever in response to 10 µg/kg LPS, but only when administered directly into the subcutaneous chamber, and not into the site contralateral to the chamber. This observation indicated that a localized formation of PGE₂ at the site of inflammation mediated a portion of the febrile response, which was induced by injection of 10 µg/kg LPS into the subcutaneous chamber. Further support for this hypothesis derived from the observation that we failed to detect elevated amounts of COX-2 mRNA in the brain of guinea pigs injected subcutaneously with 10 µg/kg LPS, whereas subcutaneous injections of 100 µg/kg LPS, as well as systemic injections of LPS (intra-arterial or intraperitoneal routes), readily caused expression of the COX-2 gene in the guinea pig brain, as demonstrated by in situ hybridization. Therefore, fever in response to subcutaneous injection of 10 µg/kg LPS may, in part, have been evoked by a neural, rather than a humoral, pathway from the local site of inflammation to the brain.

lipopolysaccharide; febrile response; prostaglandin E₂; cyclooxygenase-2; immune system-to-brain communication

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