mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F receptors and their role in controlling the release of calcitonin gene-related peptide in the rat trigeminovascular system.
Triptans, a family of 5-hydroxytryptamine (5-HT) 1B, 1D, and 1F receptor agonists, are used in the acute treatment of migraine attacks. The site of action and subtypes of the 5-HT(1) receptor that mediate the antimigraine effect have still to be identified. This study investigated the mRNA expression of these receptors and the role of 5-HT(1) receptor subtypes in controlling the release of calcitonin gene-related peptide (CGRP) in rat dura mater, trigeminal ganglion (TG), and trigeminal nucleus caudalis (TNC). The mRNA for each receptor subtype was quantified by quantitative real-time polymerase chain reaction. A high potassium concentration was used to release CGRP from dura mater, isolated TG, and TNC in vitro. The immunoreactive CGRP (iCGRP) release was measured by enzyme-linked immunoassay. The mRNA transcripts of the 3 5-HT(1) receptor subtypes were detected in the trigeminovascular system. Sumatriptan inhibited iCGRP release by 31% in dura mater, 44% in TG, and 56% in TNC. This effect was reversed by a 5-HT(1B/1D) antagonist (GR127395). The 5-HT(1F) agonist (LY-344864) was effective in the dura mater (26% iCGRP inhibition), and the 5-HT(1D) agonist (PNU-142633) had a significant effect in the TNC (48%), whereas the 5-HT(1B) agonist (CP-94253) was unable to reduce the iCGRP release in all tissues studied. We found that sumatriptan reduced the iCGRP release via activation of 5-HT(1D) and 5-HT(1F) receptor subtypes. The 5-HT(1F) receptor agonist was effective only in peripheral terminals in dura mater, whereas the 5-HT(1D) agonist had a preferential effect on central terminals in the TNC.
Department of Neurology and Danish Headache Center, Glostrup Research Institute, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Glostrup, Denmark Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, USA.
Dipak V
DV
Amrutkar
Kenneth B
KB
Ploug
Anders
A
Hay-Schmidt
Frank
F
Porreca
Jes
J
Olesen
Inger
I
Jansen-Olesen
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004388:Dura Mater / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B / Q000096:biosynthesis / Q000502:physiology*; D044346:Receptor, Serotonin, 5-HT1D / Q000096:biosynthesis / Q000502:physiology*; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism*; D014278:Trigeminal Nuclei / Q000187:drug effects / Q000378:metabolism; D000096642:Receptor, Serotonin, 5-HT1F
D015740:Calcitonin Gene-Related Peptide; D012333:RNA, Messenger; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D000096642:Receptor, Serotonin, 5-HT1F