Skip to main content
Log in

Electrophysiological evidence for a spinal antinociceptive action of dipyrone

  • Pain
  • Published:
Agents and Actions Aims and scope Submit manuscript

Abstract

Electrophysiological experiments in anesthetized cats and rats were performed in order to study the effects of dipyrone on single afferent fibers from the knee joint and on spinal cord neurons with knee joint input. The neurons were activated and/or rendered hyperexcitable by an acute inflammation in the knee joint. In the joint nerve in cats, intravenous dipyrone (25–100 mg/kg) reduced ongoing activity in 10/12 thinly myelinated afferents but only in 1/10 unmyelinated afferents; the responses to movements of the inflamed knee were reduced in 8/10 thinly myelinated but only in 3/10 unmyelinated units. The reduction of activity was significant 20–30 min after application and was maximal at 60–180 min. In the spinal cord of spinalized cats, intravenous dipyrone (25–100 mg/kg) reduced ongoing activity and/or responses to pressure onto the inflamed knee in 14/16 neurons and in non-spinalized rats similar effects were seen in 10/11 neurons. Effects on spinal cord neurons started 5–10 min after application and were maximal after 20–40 min. These data show pronounced suppression of inflammation-induced nociception by dipyrone and they suggest that the spinal cord is a major site of action of this compound.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. A. Dembinska-Kiec, A. Zmuda and J. Krupinska,Inhibition of prostaglandin synthetase by aspirin-like drugs in different microsomal preparations. InAdvances in Prostaglandin and Thromboxane Research, Vol. 1. (Eds. B. Samuelsson and R. Paoletti) pp. 99–103, Raven Press, New York 1976.

    Google Scholar 

  2. K. Brune and H. Alpermann,Non-acidic pyrazoles: Inhibition of prostaglandin production, carrageenan oedema and yeast fever, Agents and Actions13, 360–363 (1983).

    PubMed  Google Scholar 

  3. R. N. Brogden,Pyrazolone derivatives. Drugs32, 60–70 (1986).

    PubMed  Google Scholar 

  4. R. Weiss, J. Bauer, U. Goertz and R. Petry,Comparative study on absorption and metabolism of the pyrazolone derivative metamizole in man after oral and intramuscular administration. Drug Res.24, 345–348 (1974).

    Google Scholar 

  5. M. Volz and H.-M. Kellner,Kinetics and metabolism of pyrazolones (propyphenazone, aminopyrine and dipyrone). Br. J. Clin. Pharmac.10, 299S-308S (1980).

    Google Scholar 

  6. E. Z. Katz and L. Granit,Simultaneous determination of dipyrone metabolites in plasma by high-performance liquid chromatography, J. Chromatogr305, 477–484 (1984).

    PubMed  Google Scholar 

  7. C. Coersmeier, H. R. Wittenberg, U. Aehringhaus, K. W. Dreyling, B. M. Peskar, K. Brune and B. A. Peskar,Effect of anti-inflammatory and analgesic pyrazoles on arachidonic acid metabolism in isolated heart and gastric mucosa preparations. In100 years of Pyrazolone. Agents and Actions (Suppl.) Vol. 19. (Ed. K. Brune) pp. 137–154, Birkhäuser, Basel 1986.

    Google Scholar 

  8. J. C. Frölich, W. A. Rupp, R. M. Zapf and M. J. Badian.The effects of metamizol on prostaglandin synthesis in man. In100 Years of Pyrazolone. Agents and Actions (Suppl.) Vol. 19. (Ed. K. Brune) pp. 155–166, Birkhäuser, Basel 1986.

    Google Scholar 

  9. R. Lanz, B. A. Peskar and K. Brune,The effects of acidic and nonacidic pyrazoles on arachidonic acid metabolism in mouse peritoneal macrophages. In100 Years of Pyrazolone. Agents and Actions (Suppl.) Vol. 19. (Ed. K. Brune) pp. 125–135, Birkhäuser, Basel 1986.

    Google Scholar 

  10. A. Eldor, G. Polliack, I. Vlodavsky and M. Levy,Effects of dipyrone on prostaglandin production by human platelets and cultured bovine aortic endothelial cells. Thromb. Haemostas.49, 132–137 (1983).

    Google Scholar 

  11. R. J. Flower and J. R. Vane,Inhibition of prostaglandin synthetase in brain explains the antipyretic activity of paracetamol (4-acetamidophenol). Nature240, 410–411 (1972).

    PubMed  Google Scholar 

  12. H. Laburn, D. Mitchell and J. Stephen,Effects of intracerebroventricular floctafenine and indomethacin on body temperature in febrile rabbits. Br. J. Pharmacol.721, 525–528.

  13. J. R. Vane,Pain of inflammation: An introduction. InAdvances in Pain Research and Therapy, Vol. 5. (Eds. J. J. Bonica, U. Lindblom, A. Iggo, L. E. Jones and C. Benedetti) pp. 597–603, Raven Press, New York 1983.

    Google Scholar 

  14. K. Brune,Prostaglandins and the mode of action of antipyretic analgesic drugs. Am. J. Med.75, 19–23 (1983).

    Article  Google Scholar 

  15. K. Brune and R. Lanz,Mode of action of peripheral analgesics. Drug Res.34, 1060–1065 (1984).

    Google Scholar 

  16. K.-H. Carlsson, J. Helmreich and I. Jurna,Activation of inhibition from the periaqueductal grey matter mediates central analgesic effect of metamizol (dipyrone). Pain27, 373–390 (1986).

    Article  PubMed  Google Scholar 

  17. K.-H. Carlsson and I. Jurna,The role of descending inhibition in the antinociceptive effects of the pyrazolone derivatives, metamizol (dipyrone) and aminophenazone (“Pyramidon”). Naunyn-Schmiedeberg's Arch. Pharmacol.335, 154–159 (1987).

    Article  Google Scholar 

  18. L. Gelgor, S. Cartmell and D. Mitchell,Intracerebroventricular microinjections of nonsteroidal anti-inflammatory drugs abolish reperfusion hyperalgesia in the rat's tail. Pain50, 323–329 (1992).

    Article  PubMed  Google Scholar 

  19. K.-H. Carlsson, W. Monzel and I. Jurna,Depression by morphine and the non-opioid analgesic agents, metamizol (dipyrone), lysine acetylsalicylate, and paracetamol, of activity in rat thalamus neurones evoked by electrical stimulation of nociceptive afferents. Pain32, 313–326 (1988).

    Article  PubMed  Google Scholar 

  20. H.-G. Schaible and R. F. Schmidt,Time course of mechanosen-sitivity changes in articular afferents during a developing experimental arthritis. J. Neurophysiol.60, 2180–2195 (1988).

    PubMed  Google Scholar 

  21. V. Neugebauer and H.-G. Schaible,Evidence for a central component in the sensitization of spinal neurons with joint input during development of acute arthritis in cat's knee. J. Neurophysiol.64, 299–311 (1990).

    PubMed  Google Scholar 

  22. V. Neugebauer, T. Lücke and H.-G. Schaible,N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists block the hyperexcitability of dorsal horn neurons during development of acute arthritis in rat's knee joint. J. Neurophysiol.70, 1365–1377 (1993).

    PubMed  Google Scholar 

  23. H.-G. Schaible, V. Neugebauer, F. Cervero and R. F. Schmidt,Changes in tonic descending inhibition of spinal neurons with articular input during the development of acute arthritis in the cat. J. Neurophysiol.66, 1021–1032 (1991).

    PubMed  Google Scholar 

  24. H.-G. Schaible and R. F. Schmidt,Responses of fine medial articular nerve afferents to passive movements of knee joint. J. Neurophysiol.49, 1118–1126 (1983).

    PubMed  Google Scholar 

  25. C. R. Tonussi and S. H. Ferreira,Rat knee-joint carrageenin incapacitation test: An objective screen for central and peripheral analgesics. Pain48, 421–427 (1992).

    Article  PubMed  Google Scholar 

  26. L. A. Langford and R. F. Schmidt,Afferent and efferent axons in the medial and posterior articular nerves of the cat. Anat. Rec.206, 71–78 (1983).

    Article  PubMed  Google Scholar 

  27. B. Heppelmann, C. Heuss and R. F. Schmidt,Fiber size distribution of myelinated and unmyelinated axons in the medial and posterior articular nerves of the cat's knee joint. Somatosens. Res.5, 273–281 (1988).

    PubMed  Google Scholar 

  28. B. Heppelmann, A. Pfeffer, H.-G. Schaible and R. F. Schmidt,Effects of acetylsalicylic acid and indomethacin on single groups III and IV sensory units from acutely inflamed joints. Pain26, 337–351 (1986).

    Article  PubMed  Google Scholar 

  29. S. Mehta,Comparison of pethidine with sodium phenyldimethyl pyrazolone methylaminomethane sulphonate (Novalgin) and with a placebo in postoperation pain. Indian J. Anaesthesia15, 232–237 (1967).

    Google Scholar 

  30. S. R. Panday, A. P. Chaukar, A. V. Kanetkar and P. K. Sen,Use of Novalgin in the relief of post operative pain in major thoracic and cardiovascular surgery. J. Postgrad. Med.14, 142–146 (1968).

    PubMed  Google Scholar 

  31. H. A. Baar,Pyrazolone drugs in outpatient pain treatment. In100 Years of Pyrazolone, Agents and Actions (Suppl.) Vol. 19. (Ed. K. Brune) pp. 321–329, Birkhäuser, Basel 1986.

    Google Scholar 

  32. H. U. Gerbershagen,Pyrazolone drugs and their use at pain centres. In100 Years of Pyrazolone. Agents and Actions (Suppl.) Vol. 19. (Ed. K. Brune) pp. 315–319, Birkhäuser, Basel 1986.

    Google Scholar 

  33. V. Hempel,Pyrazolones in the treatment of postoperative pain. In100 Years of Pyrazolone. Agents and Actions (Suppl.) Vol. 19. (Ed. K. Brune) pp. 331–337, Birkhäuser, Basel 1986.

    Google Scholar 

  34. S. D. Mehta,A randomized double-blind placebo-controlled study of dipyrone and aspirin in post-operative orthopaedic patients. J. Int. Med. Res.14, 63–66 (1986).

    PubMed  Google Scholar 

  35. P. W. Ramwell, J. E. Shaw and R. Jessup,Spontaneous and evoked release of prostaglandins from frog spinal cord. Am. J. Physiol.211, 998–1004 (1966).

    PubMed  Google Scholar 

  36. T. J. Coderre, R. Gonzales, M. E. Goldyne, J. West and J. D. Levine,Noxious stimulus-induced increase in spinal prostaglandin E 2 is noradrenergic terminal-dependent. Neurosci. Lett.115, 253–256 (1990).

    Article  PubMed  Google Scholar 

  37. M. R. Vasco, S. L. Zirkelbach and K. J. Waite,Prostaglandins stimulate the release of substance P from rat spinal cord slices. InCentral Mechanisms for Analgesia by Acetylsalicylic Acid and (Functionally) Related Compounds. Progress in Pharmacology and Clinical Pharmacology. Vol. 10. (Eds. I. Jurna and T. L. Yaksh) pp. 69–89, G. Fischer, Stuttgart 1993.

    Google Scholar 

  38. K. U. Weithmann and H.-G. Alpermann,Biochemical and pharmacological effects of dipyrone and its metabolites in model systems related to arachidonic acid cascade. Drug Res.35, 947–952 (1985).

    Google Scholar 

  39. B. B. Lorenzetti and S. H. Ferreira,Mode of analgesic action of dipyrone: direct antagonism of inflammatory hyperalgesia. Eur. J. Pharmacol.114, 375–381 (1985).

    Article  PubMed  Google Scholar 

  40. H. Levitan and J. L. Barker,Effect of non-narcotic analgesics on membrane permeability of molluscan neurones. Nature New Biology239, 55–57 (1972).

    PubMed  Google Scholar 

  41. H. Levitan and J. L. Barker,Salicylates: A structure-activity study on its effects on membrane permeability. Science176, 1423–1425 (1972).

    PubMed  Google Scholar 

  42. F. R. Neto and T. Narahashi,Ionic mechanism of the salicylate block of nerve conduction. J. Pharmacol. Exp. Therap.199, 454–463 (1976).

    Google Scholar 

  43. F. R. Neto,Further studies on the actions of salicylates on nerve membranes. Eur. J. Pharmacol.68, 155–162 (1980).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Neugebauer, V., Schaible, H.G., He, X. et al. Electrophysiological evidence for a spinal antinociceptive action of dipyrone. Agents and Actions 41, 62–70 (1994). https://doi.org/10.1007/BF01986396

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01986396

Key words

Navigation