DUAL EFFECT OF THE SEROTONIN AGONIST, SUMATRIPTAN, ON PERIPHERAL NEUROGENIC INFLAMMATION

Background and Objectives. Sumatriptan is a novel drug for migraine he adache pain, which, on the basis of its mechanism of action, may have therapeutic potential in other pain states. Sumatriptan inhibits neuro genic inflammation in dural vessels by activating the 5-HTIB and 5-HTI D inhibitory serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes on terminals of trigeminal neurons. This study was designed to determi ne 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 affin ity, 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 f or 5-HT receptors in rat lumbar dorsal root ganglia. Rat knee joint pl asma extravasation was used to determine the effect of sumatriptan on peripheral neurogenic inflammation. Results. The mRNA for the sumatrip tan-activated receptors 5-HT1B, 5-HT1D, and 5-HT7, was detected in lum bar dorsal root ganglia. In rat knee joint, capsaicin-activated C-fibe rs stimulated plasma extravasation to 273 +/- 62% of baseline. Low-con centration sumatriptan (50 nM) significantly inhibited capsaicin-induc ed plasma extravasation to 106 +/- 6% of baseline. High-concentration sumatriptan (1 mu M) significantly enhanced capsaicin-induced plasma e xtravasation to 572 +/- 55% of baseline. Conclusions. Sumatriptan inhi bits peripheral neurogenic inflammation, probably via 5-HT1B/1D recept ors, and may be a novel therapy for inflammatory pain states. However, high concentrations (> 200 nM) may enhance neurogenic inflammation, p ossibly by activation of 5-HT7 receptors, which may explain lack of mi graine relief and excessive injection site pain in 20-30% of patients treated with sumatriptan.