The antipyretic effect of dipyrone is unrelated to inhibition of PGE2 synthesis in the hypothalamus

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 PGE2 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. PGE2 levels were determined in the plasma, CSF and hypothalamus by elisa. KEY RESULTS LPS or ET‐1 induced fever and increased CSF and hypothalamic PGE2 levels. Two hours after LPS, indomethacin reduced CSF and hypothalamic PGE2 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 PGE2 levels but did not affect fever. Dipyrone abolished both the fever and the increased CSF PGE2 levels induced by LPS or ET‐1 but did not affect the increased hypothalamic PGE2 levels. Dipyrone also reduced the increase in the venous plasma PGE2 concentration induced by LPS. CONCLUSIONS AND IMPLICATIONS These findings confirm that PGE2 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 PGE2 synthesis.