[3H]Sumatriptan binding sites in human brain: regional-dependent labelling of 5-HT1D and 5-HT1F receptors

doi:10.1016/0014-2999(95)00748-2

European Journal of Pharmacology

Volume 295, Issues 2–3, 11 January 1996, Pages 271-274

https://doi.org/10.1016/0014-2999(95)00748-2 Get rights and content

Abstract

The general properties of [³H]sumatriptan binding sites in postmortem human brain tissue sections are described. High concentrations of autoradiographic grains were seen in globus pallidus = substantia nigra > cortex > putamen > hippocampus. While 5-HT (5-hydroxytryptamine) displaced in all regions more than 90% of [³H]sumatriptan binding, the level of binding inhibited by 5-CT (5-carboxamidotryptamine) varied in each region. Although the binding inhibited by 5-CT in some regions such as globus pallidus and substantia nigra was equivalent to that obtained with 5-HT, in cortical areas, such as frontal cortex and hippocampus, a substantial level of binding insensitive to 5-CT was seen. In addition, in membrane binding assays, 10 nM metergoline displaced most [³H]sumatriptan specific binding in striatum and only 16% in frontal cortex. In the human brain sumatriptan binds to at least two 5-HT₁ receptors, 5-HT_1D and 5-HT_1F.

References (18)

F.G. Boess et al.
Molecular biology of 5-HT receptors
Neuropharmacology
(1994)
A.T. Bruinvels et al.
A comparative autoradiographic study of 5-HT_1D binding sites in human and guinea-pig brain using different radioligands
Mol. Brain Res.
(1994)
A.T. Bruinvels et al.
Localization of 5-HT_1B, 5-HT_1Dα, 5-HT_1E and 5-HT_1F receptor messenger RNA in rodent and primate brain
Neuropharmacology
(1994)
G.R. Martin et al.
Classification review
Receptors for 5-hydroxytryptamine: current perspectives on classification and nomenclature
Neuropharmacology
(1994)
A.A. Parsons
5-HT receptors in human and animal cerebrovasculature
Trends Pharmacol. Sci.
(1991)
A. Pazos et al.
The binding of serotonergic ligands to the porcine choroid plexus: characterization of a new type of serotonin recognition site
Eur. J. Pharmacol.
(1984)
A. Pazos et al.
Serotonin receptors in the human brain. III. Autoradiographic mapping of serotonin-1 receptors
Neuroscience
(1987)
S.J. Peroutka
Developments in 5-hydroxytryptamine receptor pharmacology in migraine
Neurologic Clinics: Headache
(1990)
J.R. Unnerstall et al.
Quantitative receptor autoradiography using ³H-ultrofilm: application to multiple benzodiazepine receptors

There are more references available in the full text version of this article.

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In the spinal cord of postmortem humans, using [3H]sumatriptan binding, Castro et al. [12] found suitable concentrations of 5-HT1FR in the substantia gelatinosa of the spinal cord. Low densities were also observed in spinal cord [17], Mills and Martin [18] found that there is the high densities of 5-HT1FR in the dorsal horn of the spinal cord in cat. Simmons et al confirmed the presence of 5-HT1FR mRNA of thoracic spinal cord in female WT mice, and absence in KO mice by PCR amplification [10–11].
Spasticity is a common complication in patients with spinal cord injury (SCI) and adversely affects patients’ quality of life. Little is known about the distribution of the serotonin 1F receptor (5-HT1FR) in the spinal cord, especially in relation to the spasticity caused by SCI. Adult male Wistar rats were divided into a sham-operation group and spinalized group. SCI-induced spasticity was caused by spinal transection at the second sacral segment. The spinal cord below the transection was obtained at the end of the experiment. The expression and distribution of 5-HT1FR in the spinal cord were analyzed. The results showed that the expression of 5-HT1FR (mRNA and protein) exhibited the same downward trend after spinal transection and reached the lowest expression level at 2 and 5 days, respectively. The expression of 5-HT1FR (mRNA and protein) thereafter gradually approached the levels in the sham-operation group after 60 days. Immunostaining suggested that 5-HT1FR showed particularly strong expression in the ventral horn (VH) region. The time course of 5-HT1FR mRNA downregulation is positively correlated with the development of tail spasticity after sacral spinal cord transection. There may be a connection between 5-HT1FR and the occurrence of spasticity, but elucidation of the specific mechanism needs further experimental verification.
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On the contrary, the claustrum, lateral geniculate nucleus, mammillary nucleus, and oculomotor nucleus are densely labeled in the guinea pig, but not in the rat (Lucaites et al., 2005; Waeber & Moskowitz, 1995). In the human brain, 5-HT1F receptors (i.e., [3H]-sumatriptan-binding sites insensitive to 5-CT) are present in several forebrain areas, such as layer V of the frontal, parietal, temporal, and occipital cortex, the CA1 field of the hippocampus, and the granule cell layer of the cerebellum (Lucaites et al., 2005; Pascual et al., 1996). In addition, the 5-HT1F receptor is found in significant quantities in several human brainstem nuclei such as the substantia nigra, spinal trigeminal nucleus, nucleus of the tractus solitarius, and substantia gelatinosa of the upper cervical spinal cord (Castro et al., 1997).
Almost 10 years have passed since we wrote the review on the “Distribution of 5-HT receptors in the central nervous system” in this series (Mengod, Cortés, Vilaró, & Hoyer, 2010). The number of 5-HT receptors remains the same: 14 receptor subtypes grouped in seven families. New findings are related to the identification of the phenotype of the cells expressing 5-HT receptors and their colocalization with other related neurotransmitters and neurotransmitter receptors, some in neurons, others in glial cells or astrocytes (Zhang et al., 2010). The application of immunohistochemistry adds new information about this colocalization. A number of studies are centered on the expression of 5-HT receptors in brain areas related with migraine. New labeled ligands have been developed and preferentially used for positron emission tomography studies in various pathological conditions, as such molecules are considered as potential treatments and/or biomarkers for various diseases.
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Indeed, preclinical sensitization studies using dural inflammatory soup have suggested that sumatriptan only acts on these presynaptic trigeminovascular locations (Burstein & Jakubowski, 2004; Levy et al., 2004). Yet, there is specific binding of [3H]-sumatriptan in human (Pascual, Del Arco, Romon, Del Olmo, & Pazos, 1996), cat (Mills & Martin, 1995) and guinea pig (Waeber & Moskowitz, 1995) TCC, and [3H]-zolmitriptan in the cat (Goadsby & Knight, 1997a, 1997b) TCC, which demonstrates a clear locus of action of 5-HT1B/1D receptor agonists on second-order neurons in the TCC. Also, direct microiontophoresis of 5-HT1B/1D receptor agonists, sumatriptan and zolmitriptan, results in reversible inhibition of dural stimulation-evoked and local glutamate-evoked TCC neuronal firing (Storer & Goadsby, 1997; Goadsby, Akerman, & Storer, 2001).
Migraine headache and its associated symptoms have plagued humans for two millennia. It is manifest throughout the world, and affects more than 1/6 of the global population. It is the most common brain disorder, and is characterized by moderate to severe unilateral headache that is accompanied by vomiting, nausea, photophobia, phonophobia, and other hypersensitive symptoms of the senses. While there is still a clear lack of understanding of its neurophysiology, it is beginning to be understood, and it seems to suggest migraine is a disorder of brain sensory processing, characterized by a generalized neuronal hyperexcitability. The complex symptomatology of migraine indicates that multiple neuronal systems are involved, including brainstem and diencephalic systems, which function abnormally, resulting in premonitory symptoms, ultimately evolving to affect the dural trigeminovascular system, and the pain phase of migraine. The migraineur also seems to be particularly sensitive to fluctuations in homeostasis, such as sleep, feeding and stress, reflecting the abnormality of functioning in these brainstem and diencephalic systems. Implications for therapeutic development have grown out of our understanding of migraine neurophysiology, leading to major drug classes, such as triptans, calcitonin gene-related peptide receptor antagonists, and 5-HT_1F receptor agonists, as well as neuromodulatory approaches, with the promise of more to come. The present review will discuss the current understanding of the neurophysiology of migraine, particularly migraine headache, and novel insights into the complex neural networks responsible for associated neurological symptoms, and how interaction of these networks with migraine pain pathways has implications for the development of novel therapeutics.
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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-HT₁ 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-HT₁ 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-HT₁ 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.
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Although the cardinal manifestations of Parkinson's disease (PD) are attributed to a decline in dopamine levels in the striatum, a breadth of non-motor features and treatment-related complications in which the serotonergic system plays a pivotal role are increasingly recognised. Serotonin (5-HT)-mediated neurotransmission is altered in PD and the roles of the different 5-HT receptor subtypes in disease manifestations have been investigated. The aims of this article are to summarise and discuss all published preclinical and clinical studies that have investigated the serotonergic system in PD and related animal models, in order to recapitulate the state of the current knowledge and to identify areas that need further research and understanding.
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The vasoconstrictor 5-HT1B receptors were shown to be located on the smooth muscle of meningeal blood vessels (Longmore et al., 1998) with inhibitory 5-HT1D receptors on the peripheral and central terminals of the trigeminal sensory nerves where they could modulate neuropeptide release and central trigeminal pain signal transmission (Longmore et al., 1997a). Autoradiographic studies also showed the presence of these serotonin receptors together with 5-HT1F receptors in the trigeminal dorsal horn (Pascual et al., 1996; Castro et al., 1997). 5-HT1F receptors are absent from meningeal blood vessels (Razzaque et al., 1999).
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Short communication[3H]Sumatriptan binding sites in human brain: regional-dependent labelling of 5-HT1D and 5-HT1F receptors

Abstract

Neuropharmacology

Mol. Brain Res.

Neuropharmacology

Neuropharmacology

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Neuroscience

Neurologic Clinics: Headache

Short communication
[³H]Sumatriptan binding sites in human brain: regional-dependent labelling of 5-HT_1D and 5-HT_1F receptors