THE 5-HT1D RECEPTOR ANTAGONIST GR-127,935 PREVENTS INHIBITORY EFFECTSOF SUMATRIPTAN BUT NOT CP-122,288 AND 5-CT ON NEUROGENIC PLASMA EXTRAVASATION WITHIN GUINEA-PIG DURA-MATER

The aim of this study was to examine whether GR-127,935, a 5-HT1B/1D r eceptor antagonist, blocks the inhibitory effects of sumatriptan, CP-1 22,288 and 5-carboxamidotryptamine (5-CT) on plasma protein extravasat ion, within guinea pig and rat dura mater, following electric stimulat ion of the trigeminal ganglion. Binding studies first established that GR-127,935 shows a 500-fold selectivity for 5-HT1D binding sites (lab eled by [H-3]L-694,247) versus 5-HTIF binding sites (labeled by [3H]su matriptan in the presence of 50 nM 5-carboxamidotryptamine) in guinea pig forebrain homogenates (pK(D) +/- 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 pa rtial agonist activity and inhibited dural plasma protein extravasatio n. 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 hig h as 2 mu mol/kg). Sumatriptan, CP 122,288 and 5-CT dose-responsively inhibited plasma protein extravasation. Ata dose of 2 mu mol/kg (but n ot at 0.2 mu mol/kg), GR-127,935 right-shifted the dose-response curve of sumatriptan. No significant rightward shift was observed in the do se-response of CP-122,288 and 5-CT. In rats, GR-127,935 did not show a ny significant partial agonist activity. A dose of 0.2 mu mol/kg was s ufficient 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 th e inhibition of plasma extravasation by CP-122,288 and 5-CT. Pertussis toxin reduced the inhibitory effects of both sumatriptan and 5-CT, bu t not of muscimol, known to act at GABA(A) receptors. These results su ggest that 5-CT, as well as sumatriptan, act at a receptor linked to a n inhibitory G-protein. (C) 1997 Elsevier Science Ltd.