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.
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.
Cutrer
F M
FM
Department of Neurology, Massachusetts General Hospital, Charlestown 02129, USA. cutrer@helix.mgh.harvard.edu
Yu
X J
XJ
Ayata
G
G
Moskowitz
M A
MA
Waeber
C
C
D000818:Animals; D001578:Benzopyrans / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D004388:Dura Mater / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004558:Electric Stimulation; D006168:Guinea Pigs; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D014278:Trigeminal Nuclei / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
D001578:Benzopyrans; D001798:Blood Proteins; D010069:Oxadiazoles; C112854:PNU 109291; D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C090701:GR 127935; D002211:Capsaicin