The antipyretic effect of dipyrone is unrelated to inhibition of PGE 2 synthesis in the hypothalamus

• Published in: British journal of pharmacology Vol. 162; no. 6; pp. 1401 - 1409
• Main Authors: Malvar, David do C, Soares, Denis M, Fabrício, Aline SC, Kanashiro, Alexandre, Machado, Renes R, Figueiredo, Maria J, Rae, Giles A, de Souza, Glória EP
• Format: Journal Article
• Language: English
• Published: 01.03.2011
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2010.01150.x

BACKGROUND AND PURPOSE Bacterial lipopolysaccharide (LPS) induces fever through two parallel pathways; one, prostaglandin (PG)‐dependent and the other, PG‐independent and involving endothelin‐1 (ET‐1). For a better understanding of the mechanisms by which dipyrone exerts antipyresis, we have investigated its effects on fever and changes in PGE 2 content in plasma, CSF and hypothalamus induced by either LPS or ET‐1. EXPERIMENTAL APPROACH Rats were given (i.p.) dipyrone (120 mg·kg −1 ) or indomethacin (2 mg·kg −1 ) 30 min before injection of LPS (5 µg·kg −1 , i.v.) or ET‐1 (1 pmol, i.c.v.). Rectal temperature was measured by tele‐thermometry. PGE 2 levels were determined in the plasma, CSF and hypothalamus by elisa . KEY RESULTS LPS or ET‐1 induced fever and increased CSF and hypothalamic PGE 2 levels. Two hours after LPS, indomethacin reduced CSF and hypothalamic PGE 2 but did not inhibit fever, while at 3 h it reduced all three parameters. Three hours after ET‐1, indomethacin inhibited the increase in CSF and hypothalamic PGE 2 levels but did not affect fever. Dipyrone abolished both the fever and the increased CSF PGE 2 levels induced by LPS or ET‐1 but did not affect the increased hypothalamic PGE 2 levels. Dipyrone also reduced the increase in the venous plasma PGE 2 concentration induced by LPS. CONCLUSIONS AND IMPLICATIONS These findings confirm that PGE 2 does not play a relevant role in ET‐1‐induced fever. They also demonstrate for the first time that the antipyretic effect of dipyrone was not mechanistically linked to the inhibition of hypothalamic PGE 2 synthesis.