Clinical Drug Investigation

, Volume 19, Supplement 2, pp 1–7 | Cite as

Pathogenesis and Mechanisms of Inflammation and Pain

An Overview
  • Regina M. Botting
  • Jack H. Botting
Review Article


Pain is perceived through activation of the endings of nociceptive afferent nerves by pain-producing substances released from tissue. These nerves in turn activate nociceptive nerve cells in the dorsal horn of the spinal cord through the release of excitatory amino acids and neuropeptides. The activation of the nociceptive afferents can be amplified after repetitive stimulation via the production of nitric oxide, which facilitates the release of excitatory amino acid transmitters.

Pain is one of the cardinal signs of inflammation, the response of tissue to frank or immune damage or infection. The inflammatory response is characterised by vasodilation, oedema and a marked local accumulation of white blood cells. Many intercellular messengers, or cytokines, are responsible for the various stages of inflammation, but tumour necrosis factor seems to be a significant initiator of the response.

The severe pain that accompanies inflammatory disease such as rheumatoid arthritis is caused by the action of pain-producing substances such as kinins on nociceptor neurons sensitised by locally produced prostaglandins, and perhaps sympathomimetics released from sympathetic nerves. The first-line treatment of inflammatory pain is the use of nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit the cyclo-oxygenase enzyme (COX) which produces the hyperalgesic prostaglandins from their substrate arachidonic acid. Since prostaglandins produced in inflammation are formed by an induced COX (COX-2), distinct from that which produces the cytoprotective prostaglandins, NSAIDs that selectively inhibit COX-2 may provide effective therapy without gastrotoxicity Further clinical experience is required to establish the most effective therapy for inflammatory pain.


Bradykinin Dorsal Horn Inflammatory Pain Icatibant Inflammatory Hyperalgesia 
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  1. 1.
    Munglani R, Hunt S, Jones J. The spinal cord and chronic pain. Anaesth Rev 1996; 12: 53–6Google Scholar
  2. 2.
    Dray A. Inflammatory mediators of pain. Br J Anaesth 1995; 75: 125–31PubMedCrossRefGoogle Scholar
  3. 3.
    Watkins L, Maier S, Goehler L. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain 1995; 63: 289–302PubMedCrossRefGoogle Scholar
  4. 4.
    Emery P. Pharmacology, safety data and therapeutics of COX-2 inhibitors. In: Vane J, Botting J, Botting R, editors. Improved non-steroid anti-inflammatory drugs. COX-2 enzyme inhibitors. London: Kluwer Academic and William Harvey, 1996: 229–41CrossRefGoogle Scholar
  5. 5.
    Willoughby D, Tomlinson A, Gilroy D, et al. Inducible enzymes with special reference to COX-2 in inflammation and apoptosis. In: Vane J, Botting J, Botting R, editors. Improved nonsteroid anti-inflammatory drugs. COX-2 enzyme inhibitors. London: Kluwer Academic and William Harvey, 1996: 67–83CrossRefGoogle Scholar
  6. 6.
    Ferreira S, Lorenzetti B, Correa F. Central and peripheral antialgesic actions of aspirin-like drugs. Eur J Pharmacol 1978; 53: 39–45PubMedCrossRefGoogle Scholar
  7. 7.
    Adams D, Lloyd A. Chemokines: leucocyte recruitment and activation cytokines. Lancet 1997; 349: 490–5PubMedCrossRefGoogle Scholar
  8. 8.
    Ahluwalia A, Perretti M. B1 receptors as a new inflammatory target. Could this B the 1. Trends Pharmacol Sci 1999; 16: 100–4CrossRefGoogle Scholar
  9. 9.
    Dray A, Perkins M. Bradykinin and inflammatory pain. Trends Neurosci 1993; 16: 99–104PubMedCrossRefGoogle Scholar
  10. 10.
    Ahluwalia A, Perretti M. Involvement of bradykinin B1 receptors in the polymorphonuclear leukocyte accumulation induced by IL-1beta in vivo in the mouse. J Immunol 1996; 156: 269–74PubMedGoogle Scholar
  11. 11.
    Armstrong D, Dry R, Keele C, et al. Observations on chemical excitants of cutaneous pain in man. J Physiol 1953; 120: 326–51PubMedGoogle Scholar
  12. 12.
    Vane J, Botting R. Analgesic actions of aspirin. In: Vane J, Botting R, editors. Aspirin and other salicylates. London: Chapman and Hall Medical, 1992: 166–212Google Scholar
  13. 13.
    Boyce S, Rupniak N, Carlson E, et al. Nociception and inflammatory hyperalgesia in B2 receptor knockout mice. Immunopharmacology 1996; 33: 333–5PubMedCrossRefGoogle Scholar
  14. 14.
    Ferreira S. Prostaglandins, aspirin-like drugs and analgesia. Nature (New Biol) 1972; 240: 200–3CrossRefGoogle Scholar
  15. 15.
    Bley K, Hunter J, Eglen R, et al. The role of IP prostanoid receptors in inflammatory pain. Trends Pharmacol Sci 1998; 19: 141–7PubMedCrossRefGoogle Scholar
  16. 16.
    Murata T, Ushikubi F, Masuoka T, et al. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 1997; 388: 678–82PubMedCrossRefGoogle Scholar
  17. 17.
    Poole S, Cunha F, Ferreira S. Hyperalgesia from subcutaneous cytokines. In: Watkins L, Maier S, editors. Cytokines and pain. Basel: Birkhäuser Verlag, 1998: 59–87Google Scholar
  18. 18.
    Ferreira S. Are macrophages the body’s alarm cells? Agents Actions 1980; 10: 229–30CrossRefGoogle Scholar
  19. 19.
    Vane J, Botting R. The history of anti-inflammatory drugs and their mechanism of action. In: Bazan N, Botting J, Vane J, editors. New targets in inflammation. Inhibitors of COX-2 or adhesion molecules. London: Kluwer Academic and William Harvey, 1996: 1–12Google Scholar
  20. 20.
    Vane J. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (New Biol) 1971; 231: 232–5Google Scholar
  21. 21.
    Milton A. Antipyretic actions of aspirin. In: Vane J, Botting R, editors. Aspirin and other salicylates. London: Chapman and Hall Medical, 1992: 213–44Google Scholar
  22. 22.
    Vane J, Botting R. Mechanism of action of anti-inflammatory drugs: an overview. In: Vane J, Botting J, editors. Selective COX-2 inhibitors. Pharmacology, clinical effects and therapeutic potential. London: Kluwer Academic and William Harvey, 1998: 1–17Google Scholar
  23. 23.
    Fu J-Y, Masferrer J, Seibert K, et al. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem 1990; 265: 16737–40PubMedGoogle Scholar
  24. 24.
    Xie W, Chapman J, Robertson D, et al. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA 1988; 88: 2692–6CrossRefGoogle Scholar
  25. 25.
    Kujubu D, Fletcher B, Varnum B, et al. TIS 10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 1991; 266: 12866–72PubMedGoogle Scholar
  26. 26.
    Botting J. Nonsteroidal anti-inflammatory agents. Innovative therapies for rheumatoid arthritis [Internet conference] Jun 15–Sep 30, 1998. Available from Telesymposium Proceedings®, Barcelona: Prous ScienceGoogle Scholar
  27. 27.
    Kamali F. Rofecoxib. Curr Opin CPNS Invest Drugs 1999; 1: 126–31Google Scholar
  28. 28.
    Wallace J, Chin B. Celecoxib. Curr Opin CPNS Invest Drugs 1999; 1: 132–41Google Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • Regina M. Botting
    • 1
  • Jack H. Botting
    • 2
  1. 1.The William Harvey Research Institute, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield CollegeLondonEngland
  2. 2.LondonEngland

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