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-109 291 [(S)-(-)-1-[2-[4-(4-methoxyphenyl)-1- piperazinyl]ethyl]-N-nethyl-isochroman-6-carbox-amide], a receptor agonist showing 5000-fold selectivity for primate 5-HTT1D versus 5-HT1B receptors ( Ennis et al., J. Med. Chem. 41, 2180-2183), on dural neurogenic inflammatio n and on c-fos like immunoreactivity within trigeminal nucleus caudalis evo ked by electrical and chemical activation of trigeminal afferents, respecti vely. Subcutaneous injection of PNU-109 291 in male guinea pigs dose-depend ently reduced dural extravasation of [I-125]-labeled bovine serum albumin e voked 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-127 935 (greater than or equal to 2 mu mol k g(-1) i.v.) prevented this effect. In addition, the number of c-fos immunor eactive cells within guinea pig trigeminal nucleus caudalis induced by chem ical meningeal stimulation (intracisternally administered capsaicin) was re duced by more than 50% with PNU-109 291 (greater than or equal to 122.2 nmo l 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 n ociception in these guinea pig models. Since 5-HT1D receptor mRNA and prote in 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. (C) 1999 Elsevier Science Ltd. All rights reserved.