Effects of PNU-109,291, a selective 5-HT1D receptor agonist, on electrically induced dural plasma extravasation and capsaicin-evoked c-fos immunoreactivity within trigeminal nucleus caudalis.

Abstract

We studied the effects of PNU-109291 [(S)-(-)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methyl-isoc hroman-6-carboxamide], a receptor agonist showing 5000-fold selectivity for primate 5-HT1D versus 5-HT1B 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-109291 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-HT1B/1D receptor antagonist GR-127935 (> or = 2 micromol 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-109291 (> or = 122.2 nmol kg(-1) administered s.c. 45 min before and 15 min after capsaicin). These data indicate that the 5-HT1D receptor subtype plays a significant role in suppressing meningeal neurogenic inflammation and attenuating trigeminal nociception in these guinea pig models. Since 5-HT1D receptor mRNA and protein are expressed in trigeminal ganglia but not vascular smooth muscle, the 5-HT1D receptor subtype may become a useful therapeutic target for migraine and related headaches.

• Authors: F M Cutrer, X J Yu, G Ayata, M A Moskowitz, C Waeber
• Journal: Neuropharmacology (Neuropharmacology) Vol. 38 Issue 7 Pg. 1043-53 (Jul 1999) ISSN: 0028-3908 [Print] England
• PMID: 10428423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzopyrans
• Blood Proteins
• Oxadiazoles
• PNU 109291
• Piperazines
• Proto-Oncogene Proteins c-fos
• Receptor, Serotonin, 5-HT1D
• Receptors, Serotonin
• Serotonin Antagonists
• Serotonin Receptor Agonists
• GR 127935
• Capsaicin

Topics

• Animals
• Benzopyrans (pharmacokinetics, pharmacology)
• Binding, Competitive
• Blood Pressure (drug effects)
• Blood Proteins (metabolism)
• Capsaicin (pharmacology)
• Dura Mater (drug effects, immunology, metabolism)
• Electric Stimulation
• Guinea Pigs
• Male
• Oxadiazoles (pharmacology)
• Piperazines (pharmacokinetics, pharmacology)
• Proto-Oncogene Proteins c-fos (metabolism)
• Receptor, Serotonin, 5-HT1D
• Receptors, Serotonin (drug effects, metabolism)
• Serotonin Antagonists (pharmacology)
• Serotonin Receptor Agonists (pharmacokinetics, pharmacology)
• Trigeminal Nuclei (drug effects, immunology, metabolism)