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

Abstract

BACKGROUND AND PURPOSEBacterial 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 APPROACHRats were given (i.p.) dipyrone (120 mg·kg , 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 RESULTSLPS 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 IMPLICATIONSThese 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.

Dipyrone metabolite 4‐MAA induces hypothermia and inhibits PGE2‐dependent and ‐independent fever while 4‐AA only blocks PGE2‐dependent fever

“…The current study showed for the first time that the fever induced by Tsv was not followed by an increase in PGE 2 concentration in either the CSF or hypothalamus. Corroborating with previous findings from our lab, dipyrone, but not indomethacin, inhibited Tsv‐induced fever suggesting that Tsv induces fever through a PGE 2 ‐independent pathway (Pessini et al ., ) and that dipyrone has additional antipyretic mechanisms (Malvar et al ., ). Moreover, among the dipyrone metabolites, 4‐MAA was the only one able to inhibit the PGE 2 ‐independent fever induced by Tsv, while 4‐MAA and 4‐AA were the main active antipyretic metabolites of dipyrone on LPS‐induced fever.…”

“…Corroborating with this idea, dipyrone has been shown to inhibit PGE 2 synthesis in vivo by COX inhibition through two of its metabolites, 4‐MAA and 4‐AA, indicating that these may be the active metabolites of dipyrone (Hinz et al ., ; Pierre et al ., ). However, a significant body of evidence from our group has demonstrated that the antipyretic mechanism of dipyrone does not only relate to PGE 2 synthesis inhibition (Souza et al ., ; Pessini et al ., ; Malvar et al ., ). In addition, unlike other NSAIDs, at high doses dipyrone induces hypothermia by an unknown mechanism.…”

“…Some authors have proposed that LPS induces fever via the PGE2-dependent and -independent pathways (Strijbos et al, 1992;Fabricio et al, 2006a;Malvar et al, 2011). The first pathway requires cytokine synthesis/ release and subsequent PGE2 synthesis (via COX-2) in the preoptic area of the anterior hypothalamus (POA/AH) (Lazarus et al, 2007;Roth et al, 2009; for review Morrison and Nakamura, 2011).…”

“…The second pathway is PGE2independent and seems to be orchestrated by PFPF, CRF and ET-1 (Zampronio et al, 2000;Fabricio et al, 2006a). Although a PGE2-independent pathway is involved in LPS-induced fever, non-steroidal anti-inflammatory drugs (NSAIDs) dose-dependently reduce this response (Fabricio et al, 2005;Soares et al, 2006;Malvar et al, 2011). Moreover, mice deficient in prostanoid EP3 receptors (for receptor nomenclature see Alexander et al, 2013) do not develop fever in response to LPS (Oka et al, 2003), suggesting a crucial role for PGE2 in the development of fever induced by LPS.…”

Cannabinoid CB1 receptors mediate the effects of dipyrone

“…The presence of the dipyrone metabolites 4‐MAA and 4‐AA in cerebrospinal fluid and the hypothalamus was associated with inhibition of PGE 2 synthesis and a reduction in lipopolysaccharide‐induced fever; however, 4‐MAA has also been shown to be antipyretic in PGE 2 ‐independent fever induced by Tityus serrulatus venom . This suggests that 4‐MAA is responsible for the PGE 2 ‐independent antipyretic activity of dipyrone because it was not mechanistically linked to the inhibition of hypothalamic PGE 2 synthesis . Both dipyrone and cannabinoid agonist treatment evoked hypothermia and a CB 1 receptor antagonist blocked the analgesic, hypolocomotion and catalepsy responses to dipyrone.…”