We studied the effects of PNU-109 291 [(S)-(-)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methyl-isochroman-6-carboxamide], a receptor agonist showing 5000-fold selectivity for primate 5-HT(1D) versus 5-HT(1B) receptors (Ennis et al., J. Med. Chem. 41, 2180-2183), on dural neurogenic inflammation and on c-fos like immunoreactivity within trigeminal nucleus caudalis evoked by electrical and chemical activation of trigeminal afferents, respectively. Subcutaneous injection of PNU-109 291 in male guinea pigs dose-dependently reduced dural extravasation of [125I]-labeled bovine serum albumin evoked by trigeminal ganglion stimulation with an IC50 of 4.2 nmol kg-1. A dose of 73.3 nmol kg-1 blocked the response completely. The selective 5-HT(1B/1D) receptor antagonist GR-127 935 (≥2 μmol kg-1 i.v.) prevented this effect. In addition, the number of c-fos immunoreactive cells within guinea pig trigeminal nucleus caudalis induced by chemical meningeal stimulation (intracisternally administered capsaicin) was reduced by more than 50% with PNU-109 291 (≥122.2 nmol kg-1 administered s.c. 45 min before and 15 min after capsaicin). These data indicate that the 5-HT(1D) receptor subtype plays a significant role in suppressing meningeal neurogenic inflammation and attenuating trigeminal nociception in these guinea pig models. Since 5-HT(1D) receptor mRNA and protein are expressed in trigeminal ganglia but not vascular smooth muscle, the 5-HT(1D) receptor subtype may become a useful therapeutic target for migraine and related headaches. Copyright (C) 1999 Elsevier Science Ltd.
- 5-HT receptors
- Neurogenic inflammation
- Vascular headache
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience