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

Abstract

BACKGROUND AND PURPOSEThe antipyretic and hypothermic prodrug dipyrone prevents PGE2-dependent and -independent fever induced by LPS from Escherichia coli and Tityus serrulatus venom (Tsv) respectively. We aimed to identify the dipyrone metabolites responsible for the antipyretic and hypothermic effects. EXPERIMENTAL APPROACHMale Wistar rats were treated i.p. with indomethacin (2 mg·kg ) or saline. Rectal temperatures were measured by tele-thermometry and dipyrone metabolite concentrations determined in the plasma, CSF and hypothalamus by LC-MS/MS. PGE2 concentrations were determined in the CSF and hypothalamus by ELISA. KEY RESULTSIn contrast to LPS, Tsv-induced fever was not followed by increased PGE2 in the CSF or hypothalamus. 4-AA in the hypothalamus, CSF and plasma. These metabolites reduced LPS-induced fever and the PGE2 increase in the plasma, CSF and hypothalamus. Only 4-MAA inhibited Tsv-induced fever. The higher doses of dipyrone and 4-MAA also induced hypothermia. CONCLUSIONS AND IMPLICATIONSThe presence of 4-MAA and 4-AA in the CSF and hypothalamus was associated with PGE2 synthesis inhibition and a decrease in LPS-induced fever. 4-MAA was also shown to be an antipyretic metabolite for PGE2-independent fever induced by Tsv suggesting that it is responsible for the additional antipyretic mechanism of dipyrone. Moreover, 4-MAA is the hypothermic metabolite of dipyrone. Abbreviations4-AA, 4-aminoantipyrine; 4-AAA, 4-acethylaminoantipyrine; 4-FAA, 4-formylaminoantipyrine; 4-MAA, 4-methylaminoantipyrine; aCSF, artificial CSF; CRF, corticotrophin-releasing factor; ET-1, endothelin-1; NSAID, non-steroidal anti-inflammatory drugs; PFPF, preformed pyrogenic factor; POA/AH, preoptic area of the anterior hypothalamus; rT, rectal temperature; Tsv, Tityus serrulatus venom

Thymus algeriensis and Thymus fontanesii: Chemical Composition, In Vivo Antiinflammatory, Pain Killing and Antipyretic Activities: A Comprehensive Comparison

“…This response is elicited by exogenous pyrogens and promoted by the endogenous ones such as IL-1β, IL-6, TNF-α, endothelin-1 (ET-1), corticotrophin release factor (CRF), bradykinin, preformed pyrogenic factor (PFPF), and prostaglandin E2 (PGE2) [24]. PGE2-dependent fever results mainly by the action of the activated cyclooxygenase enzymes in the preoptic zone of the hypothalamus [25]. Brewer's yeast injection in mice raised their rectal body temperature when measured 18 h following the injection (Table 3).…”

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; 59,60 however, 4-MAA has also been shown to be antipyretic in PGE 2 -independent fever induced by Tityus serrulatus venom. 59 This suggests that 4-MAA is responsible for the PGE 2 -independent antipyretic activity of dipyrone 59 because it was not mechanistically linked to the inhibition of hypothalamic PGE 2 synthesis. 60 Both dipyrone and cannabinoid agonist treatment evoked hypothermia and a CB 1 receptor antagonist blocked the analgesic, hypolocomotion and catalepsy responses to dipyrone.…”

Effects of metabolites of the analgesic agent dipyrone (metamizol) on rostral ventromedial medulla cell activity in mice

“…A recent study suggested that a CB1 receptor inverse agonist and an anti-sense oligonucleotide against CB1 receptors reversed the anti-hyperalgesic effect of 3, but not that of dipyrone or 2 (Dos Santos et al, 2014). Finally, it was reported that 2 induced hypothermia and inhibited PGE 2 -dependent and -independent fever, while 3 only inhibited PGE 2 -dependent fever (Malvar et al, 2014).…”