A STUDY OF THE MECHANISM OF ACTION OF THE MILD ANALGESIC DIPYRONE

The mechanism of action for the mild analgesics is controversial. Whil e 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 neur al pathways to produce analgesia. This class of drugs also possesses a ntipyretic activity. We examined the antipyretic effect of one such dr ug, dipyrone, because this might elucidate the mechanism of its analge sic activity. In rats implanted with a femoral vein catheter and a can nula guide tube aimed towards the organum vasculosum laminae terminali s (OVLT) in the brain, an i.v. injection of 2 mu g/kg interleukin-1 be ta (IL-1 beta) produced a fever of 0.38 +/- 0.07 degrees C while an in jection of 20 ng prostaglandin El (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 wi th the immunoadjuvant, zymosan, the IL-1 beta fevers were enhanced to equal those induced by PGE. Only 0.1 mu g/kg, i.v. IL-1 beta raised bo dy 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; howe ver, the PGE fever remained unaffected by this treatment with dipyrone . Thus, dipyrone treatment blocks IL-1 beta fever where synthesis of p rostaglandin is a crucial step in the febrile process, but it has no e ffect on PGE fever where synthesis is bypassed. This suggests that dip yrone, probably through its active metabolites, inhibits prostaglandin synthesis to induce antipyresis and, by analogy, analgesia as well.