Differential Distribution of 5Ht 1D -and 5HT 1B -Immunoreactivity within the Human Trigemino-Cerebrovascular System: Implications for the Discovery of New Antimigraine Drugs
Restricted accessResearch articleFirst published online December, 1997
Differential Distribution of 5Ht 1D -and 5HT 1B -Immunoreactivity within the Human Trigemino-Cerebrovascular System: Implications for the Discovery of New Antimigraine Drugs
Sumatriptan, a 5HT1B/1D-receptor agonist, is clinically effective as an antimigraine agent. Its therapeutic action may result partly from vasoconstriction of excessively dilated cranial blood vessels (a 5HT1B-receptor mediated response). The antimigraine activity of sumatriptan may also result from inhibition of the release of vasoactive neuropeptides from trigeminal sensory fibres within the meninges. The identity of the 5HT1B/1D-receptor subtype mediating this effect is unknown. Using 5HT1D- and 5HT1B-receptor-specific antibodies we have demonstrated a differential distribution of these receptor subtypes within the human trigemino-cerebrovascular system. Only 5HT1B-receptor protein was detected on dural arteries. In contrast, only 5HT1D-receptor protein was detected on trigeminal sensory neurones including peripheral and central projections to dural blood vessels and to the medulla. Within the medulla 5HT1D-receptor protein was confined to discrete areas associated with the trigeminal sensory system. These findings have important implications for the design of new antimigraine drugs.
JansenIUddmanREkmanROlesenJOttosonAEdvinssionLDistribution and effects of neuropeptide Y, vasoactive intestinal peptide, substance P and calcitonin gene-related peptide in human middle meningeal arteries: comparison with cerebral and temporal arteries.
Peptides1992;
13:
52736
2.
FeindelWPenfieldWMcNaughtonFThe tentorial nerves and localisation of intracranial pain in man.Neurology1969;
10:
555–63
3.
RayBSWolffHGExperimental studies on headache. Pain sensitive structures of the head and their significance in headache.Arch Surg1940;
41:
813–56
4.
MartinsIPBaetaEPaivaTCampoTGomesLHeadaches during intracranial endovascular procedures: a possible model of vascular headache.Headache1993;
33:
227–33
5.
UddmanREdvinssonI.EkmanRKingmanTMcCullochJInnervation of the feline cerebral vasculature by nerve fibres containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P.Neurosci Lett1985;
62:
131–6
6.
MaybergMRZervasNTMoskowitzMATrigeminal projections to supratentorial pial and dural blood vessels in cats demonstrated by horseradish peroxidase histochemistry.J Comp Neurol1984;
223:
46–56
7.
SaitoKGreenbergSMoskowitzMATrigeminal origin of -preprotachykinin products in feline pial blood vessels.Neurosci Lett1987;
76:
69–73
8.
ArrabMARDelgadoTWiklundISvengaardNABrain stem terminations of the trigeminal and upper spinal innervation of the cerebrovascular system.J Cerebrovasc Blood Flow Metab1988;
8:
54–63
9.
SaltTEHillRGNeurotransmitter candidates of somato-sensory primary afferent fibres.Neuroscience1983;
10:
1083–103
10.
HumphreyPPAFeniukWMode of action of the anti-migraine drug sumatriptan,
Trends Pharmacol Sci1991;
12:
4446
11.
MoskowitzMANeurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine.Trends Pharmacol Sci1992;
13:
307–12
12.
ShepheardSI.WilliamsonDJWilliamsJHillRGHargreavesRJComparison of the effects of sumatriptan and the NK antagonist CP-99,994 on plasma protein extravasation in dura mater and c-fos mRNA expression in trigeminal nucleus caudalis of rats.Neuropharmacology1995;
34:
255–61
13.
GoadsbyPJEdvinssonLEkmanRVasoactive peptide release in the extracerebral circulation of humans during migraine headache.Ann Neurol1990;
28:
183–7
14.
HartigPRBranchekTAWeinshankRLA subfamily of 5HT1D receptor genes.Trends Pharmacol Sci1992;
13:
152–9
15.
HartigPRHoverDHumphreyPPAMartinGRAlignment of the receptor nomenclature with the human genome: classification of 5HT1B and 5HT1D receptor subtypes.Trends Pharmacol Sci1996;
17:
103–5
16.
HamelEFanELinvilleDTingVVillemurcJ-GChiaLSExpression of mRNA for the serotonin 5-hydroxytryptamine1D receptor subtype in human and bovine cerebral arteries.Mol Pharmacol1993;
44:
242–6
17.
UllmerCSchmuckKKalkmanLubbertHExpression of serotonin receptor mRNAs in blood vessels.FEBS Left1995;
370:
215–21
RebeckGWMaynardK1HymanBTMoskowitzMASelective 5HT1D/1B serotonin receptor gene expression in trigeminal ganglia: implications for antimigraine drug development.Proc Natl Acad Sci USA1994;
94:
3666–9
20.
Bouchelet1CohenZCaseBSequelaPHamelEDifferential expression of sumatriptan-sensitive 5-hydroxytryptamine receptors in human trigeminal ganglia and cerebral blood vessels.Mol Pharmacol1996;
50:
219–23
21.
ShiSRKeyMEKalraKLAntigen retrieval in formalin fixed paraffin embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections.J Histochem Cytochem1991;
39:
741–8
22.
SmithDShawDHopkinsRMcAllisterGHillRGSirinathsinghjiDJSLongmoreJCharacterisation of 5HT1D- and 5HT1B-receptor subtype specific antibodies.
J Neurosci Methods1997
(in press)
23.
YuX-IWaeberCCastanonNScearceKHenRMacorJE5-Carboxamido-trytamine, CP-122,288 and dihydroergotamine but not sumatriptan, CP-93,129, and serotonin-5 O carboxymethyl-glycl-tyrosinamide block dural plasma protein extravasation in knockout mice that lack 5-hydroxy-tryptamine1B receptors.Mol Pharmacol1996;
49:
761–5
MolderingsGJFrolichDLikunguJGothertMInhibition of noradrenaline release via presynaptic 5HT1D-receptors.Naunyn Schmiedebergs Arch Pharmacol1996;
353:
272–80
26.
TorvikAAfferent connections to the sensory trigeminal nuclei, the nucleus of the solitary tract and adjacent structures: an experimental study in the rat.J Comp Neurol1956;
106:
51–142
27.
MillsAMartinGRAutoradiographic mapping of [3H]suma-triptan binding in cat brain stem and spinal cord.Eur J Pharmacol1995;
280:
175–8
28.
GoadsbyPJKnightYEDirect evidence for central. sites of action of zolmitriptan (311C90): an autographic study, in cat.Cephalalgia1997;
17:
153–8
29.
WaeberCMoskowitzM[6H]Sumatriptan labels both 5HT1D and 5HT1B-receptor binding sites in the guinea-pig brain: an autoradiographic study. Naunyn Schmiedeberg.Arch Pharmacol1995;
352:
263–75
30.
TattersallFDRycroftWFrancisBPearceDMercantKMacLeodAMTachykinin NK1 receptor antagonists act centrally to inhibit emesis induced by the chemother peutic agent cisplatin in ferrets.Neuropharmacology996;
35:
1121–9
31.
GoadsbyPJCentral and peripheral 5-hydroxytryptamine receptor effects: what have we learnt? In:
SandlerMFerrariMDHarnettS, editors.
Migraine: pharmacology and genetics.
London:
Chapman & Hall,1996:
6786
32.
MantyhPWDeMasterEMalhortaAGhilardiJRRogersSDMantyhCRReceptor endocytosis and dendrite reshaping in spinal neurones after somatosensory stimulation.Science1995;
268:
1629–32
33.
FerrariMDGijsmaHBlockCAKramerMSMatzura-WolfeDTealJDDouble-blind, placebo-controlled, dose-finding study of rizatriptan (MK-0462) in acute migraine.
American Association of the Study of Headache,
San Diego, CA,
31st May to 2nd June 1996
34.
CumberbatchMJHillRGHargreavesRJRizatriptan has central antinociceptive effects against durally evoked responses.Eur J Pharmacol1997;
328:
37–40
