The 5-HT1D receptor antagonist GR-127,935 prevents inhibitory effects of sumatriptan but not CP-122,288 and 5-CT on neurogenic plasma extravasation within guinea pig dura mater

Abstract

The aim of this study was to examine whether GR-127,935, a 5-HT1B/1D receptor antagonist, blocks the inhibitory effects of sumatriptan, CP-122,288 and 5-carboxamidotryptamine (5-CT) on plasma protein extravasation, within guinea pig and rat dura matter, following electric stimulation of the trigeminal ganglion. Binding studies first established that GR-127,935 shows a 500-fold selectivity for 5-HT1D binding sites (labeled by [3H]L-694,247) versus 5-HT1F binding sites (labeled by [3H]sumatriptan in the presence of 50 nM 5-carboxamidotryptamine) in guinea pig forebrain homogenates (pKD +/- SD = 7.0 +/- 0.2 at 5-HT1F sites and 9.7 +/- 0.1 at 5-HT1D sites). In guinea pigs, GR-127,935 showed partial agonist activity and inhibited dural plasma protein extravasation. Increasing doses of GR-127,935 reversed the effect of sumatriptan, but did not affect the action of 5-CT and CP-122,288 (at a dose as high as 2 mumol/kg). Sumatriptan, CP 122,288 and 5-CT dose-responsively inhibited plasma protein extravasation. At a dose of 2 mumol/kg (but not at 0.2 mumol/kg), GR-127,935 right-shifted the dose-response curve of sumatriptan. No significant rightward shift was observed in the dose-response of CP-122,288 and 5-CT. In rats, GR-127,935 did not show any significant partial agonist activity. A dose of 0.2 mumol/kg was sufficient to right-shift the dose-response curve of sumatriptan. These data suggest that sumatriptan inhibits neurogenic inflammation via 5-HT1D alpha receptors in guinea pigs and 5-HT1D beta (5-HT1B) receptors in rats. Additional receptor subtypes are likely to be involved in the inhibition of plasma extravasation by CP-122,288 and 5-CT. Pertussis toxin reduced the inhibitory effects of both sumatriptan and 5-CT, but not of muscimol, known to act at GABAA receptors. These results suggest that 5-CT, as well as sumatriptan, act at a receptor linked to an inhibitory G-protein.