A study of the mechanism of action of the mild analgesic dipyrone.
The mechanism of action for the mild analgesics is controversial. While some have proposed that they inhibit prostaglandin synthesis in the central nervous system to interfere with nociceptive mediators in the brain, others have proposed that they act directly on nociceptive neural pathways to produce analgesia. This class of drugs also possesses antipyretic activity. We examined the antipyretic effect of one such drug, dipyrone, because this might elucidate the mechanism of its analgesic activity. In rats implanted with a femoral vein catheter and a cannula guide tube aimed towards the organum vasculosum laminae terminalis (OVLT) in the brain, an i.v. injection of 2 micrograms/kg interleukin-1 beta (IL-1 beta) produced a fever of 0.38 +/- 0.07 degrees C while an injection of 20 ng prostaglandin E1 (PGE) into the OVLT produced a fever of 1.18 +/- 0.18 degrees C. Dipyrone (25 mg/kg, i.v.) decreased the IL-1 beta fever but had no effect on the PGE fever. After pretreatment with the immunoadjuvant, zymosan, the IL-1 beta fevers were enhanced to equal those induced by PGE. Only 0.1 micrograms/kg, i.v. IL-1 beta raised body temperature by 1.20 +/- 0.10 degrees C. An increased dose of dipyrone (50 mg/kg, i.v.) was required to attenuate this IL-1 beta fever; however, the PGE fever remained unaffected by this treatment with dipyrone. Thus, dipyrone treatment blocks IL-1 beta fever where synthesis of prostaglandin is a crucial step in the febrile process, but it has no effect on PGE fever where synthesis is bypassed. This suggests that dipyrone, probably through its active metabolites, inhibits prostaglandin synthesis to induce antipyresis and, by analogy, analgesia as well.
Shimada
S G
SG
John B. Pierce Foundation Laboratory, Yale University School of Medicine, New Haven, CT 06519.
Otterness
I G
IG
Stitt
J T
JT
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D002552:Cerebral Ventricles; D004177:Dipyrone / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005268:Femoral Vein; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D011458:Prostaglandins E / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D007375:Interleukin-1; D011458:Prostaglandins E; D004177:Dipyrone