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Dual Effect of the Serotonin Agonist, Sumatriptan, on Peripheral Neurogenic Inflammation
  1. Pamela A. Pierce, M.D., Ph.D.*,
  2. Guo-Xi Xie, M.D., Ph.D.,
  3. Stephen J. Peroutka, M.D., Ph.D. and
  4. Jon D. Levine, M.D., Ph.D.
  1. *Departments of Anesthesia and
  2. Medicine, University of San Francisco, San Francisco, California, and
  3. Spectra Biomedical, Inc., Menlo Park, California
  1. Reprint requests: Pamela A. Pierce, M.D., Ph.D., Department of Anesthesia, Box 0648, University of California San Francisco, San Francisco, CA 94143-0648.


Background and Objectives Sumatriptan is a novel drug for migraine headache pain, which, on the basis of its mechanism of action, may have therapeutic potential in other pain states. Sumatriptan inhibits neurogenic inflammation in dural vessels by activating the 5-HTIB and 5-HTID inhibitory serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes on terminals of trigeminal neurons. This study was designed to determine the role of sumatriptan in peripheral pain mechanisms by detecting whether 5-HT1B and 5-HT1D receptors and the recently cloned excitatory 5-HT7 receptor, for which sumatriptan displays moderate binding affinity, are present in peripheral sensory neurons, and by determining the effect of sumatriptan on peripheral neurogenic inflammation.

Methods A polymerase chain reaction (PCR) technique was used to detect mRNA for 5-HT receptors in rat lumbar dorsal root ganglia. Rat knee joint plasma extravasation was used to determine the effect of sumatriptan on peripheral neurogenic inflammation.

Results The mRNA for the sumatriptan-activated receptors 5-HT1B, 5-HT1D, and 5-HT7, was detected in lumbar dorsal root ganglia. In rat knee joint, capsaicin-activated C-fibers stimulated plasma extravasation to 273 ± 62% of baseline. Low-concentration sumatriptan (50 nM) significantly inhibited capsaicin-induced plasma extravasation to 106 ± 6% of baseline. High-concentration sumatriptan (1 μM) significantly enhanced capsaicin-induced plasma extravasation to 572 ± 55% of baseline.

Conclusions Sumatriptan inhibits peripheral neurogenic inflammation, probably via 5-HT1B/1D receptors, and may be a novel therapy for inflammatory pain states. However, high concentrations (> 200 nM) may enhance neurogenic inflammation, possibly by activation of 5-HT7 receptors, which may explain lack of migraine relief and excessive injection site pain in 20-30% of patients treated with sumatriptan.

  • serotonin
  • 5-HT receptors
  • sumatriptan
  • neurogenic inflammation
  • plasma extravasation
  • peripheral C-fibers

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  • Supported by National Institutes of Health Grant 1R41NS-33392-01 and Bank of America Giannini Foundation.

    Dr. Pierce received first place in the 1995 American Society of Regional Anesthesia Resident Research Competition for this manuscript.