Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The distribution of perikarya showing substance P- (SP) or calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) in the rat trigeminal ganglion (TG) were investigated by means of immunohistochemical methods. Approximately 50% of the perikarya contain CGRP while SP-LI was observed in 1/3 of the cells. IR fibres were seen to leave the ganglion via the ophthalmic, maxillary, and mandibular nerves. The combination of peptide histochemistry and retrograde labelling of cells in the ganglion following injection of a fluorescent tracer into the pineal gland reveals that few SP- or CGRP-LI trigeminal neurons innervate the pineal gland. In contrast, the vast majority of perikarya in the TG were labelled upon application of the tracer to the meningeal surface supporting the view that meninges and meningeal arteries in rodents are heavily innervated by SP- and CGRP-LI trigeminal neurons.
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PMID:Substance P- and calcitonin gene-related peptide-like immunoreactive neurons in the rat trigeminal ganglion--with special reference to meningeal and pineal innervation. 137 81

Rats chronically implanted with intrathecal catheters received intrathecal injections (10 microliters followed by 10 microliters saline flush) of either saline (n = 5), somatostatin (100 micrograms, n = 10), the somatostatin analog BIM 23003 (100 micrograms, n = 5), the somatostatin analog SMS 201-995 (100 micrograms, n = 5), the substance P analog [D-Pro2, D-Trp7,9] SP (10 micrograms, n = 10), or dynorphin A (1-17) (20 nmol, n = 8). These doses (somatostatin, substance P and dynorphin A) were selected based on previous studies in which they caused significant motor deficits. Effects on thermal cutaneous nociception, behavior, motor function and spinal cord histopathology were evaluated. All peptides caused severe neurotoxicity, evidenced by flaccid hind leg paralysis and lumbar spinal neuronal degeneration, which was accompanied by an inflammatory reaction in meninges and spinal gray matter. Histopathological changes had developed within 24 h after injection of somatostatin, substance P analog and dynorphin A, showing mild to severe neuronal degeneration and mild inflammatory responses in spinal cord and meninges. Significant antinociceptive effects, due to severe neurotoxic effects, were only observed following intrathecal injection of SMS 201-995 and the substance P analog. Potential neurotoxic mechanisms of the different peptides are discussed.
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PMID:Intrathecal somatostatin, somatostatin analogs, substance P analog and dynorphin A cause comparable neurotoxicity in rats. 171 Nov 72

The overall distribution of substance P (SP) immunoreactive (IR) nerves surrounding the cerebral arteries of the bent-winged bat were investigated immunohistochemically. In this microchiropteran species, the walls from the vertebral artery to the caudal part of the basilar artery have considerably well-developed plexuses of SP-IR nerves, whereas no demonstrable SP-IR fibers were found in the rostral part of the basilar artery, and in more rostrally located arteries the nerve supply was very sparse or occasionally lacking. This innervation pattern has not yet been established for the cerebral arterial systems of other mammals that have been studied under normal conditions, but it is very similar to the pattern of SP-IR innervation observed in the guinea pig and cat of which the trigeminal ganglia have been destroyed. From the combination of this and other immunohistochemical findings, it is suggested that SP-IR nerves innervating the vertebral and basilar arteries of the bent-winged bat originate from the upper cervical dorsal root ganglia (DRG) and enter the cranial cavity along the vertebral artery and through the meninges.
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PMID:An immunohistochemical study on the innervation of SP-IR nerves in the cerebral arteries of the bent-winged bat. 246 74

Double staining immunohistochemistry was used to investigate the origin and projection of nerves with substance P (SP) immunoreactivity (-IR) in the walls of the major cerebral arteries in two microchiropteran species. In the greater horseshoe bat, most of the cerebral perivascular nerves with SP-IR did not exhibit calcitonin gene-related peptide (CGRP)-IR, but emitted bright immunofluorescence for vasoactive intestinal polypeptide (VIP). In this species, a large number of cell bodies with both SP- and VIP-IR were observed in many cranial ganglia along various branches of the facial and glossopharyngeal nerves. There were no cell bodies immunoreactive for either SP and VIP in the two sensory (trigeminal and upper cervical dorsal root), two sympathetic (superior cervical and stellate), or two vagal (superior and jugular) ganglia. In addition, several thick fiber bundles with both SP- and VIP-IR were present in the wall of the cerebral carotid artery, and descended progressively reaching as far as the middle part of the basilar artery (BA). These and other findings suggest that SP-immunoreactive nerves with VIP-IR but not CGRP-IR, which contribute to the rich innervation of the vertebrobasilar system in the greater horseshoe bat, originate from neurons with the same combination of peptide-IR in the major or local facial or glossopharyngeal parasympathetic ganglia, and enter the cranial cavity along the internal carotid artery. In the bent-winged bat, however, cerebral perivascular SP-immunoreactive nerves, as well as SP-immunoreactive neurons within the trigeminal and upper cervical dorsal root ganglia (uCDRG), showed neither CGRP-IR nor VIP-IR, and were mostly confined to the caudal BA and the vertebral artery (VA). These observations, in addition to the projection of this nerve type to the BA via the VA as fiber bundles, or through the meninges, indicate that the principal source of the cerebrovascular SP-immunoreactive innervation in this species is the uCDRG.
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PMID:Nature and origin of cerebrovascular nerves with substance P immunoreactivity in bats (Mammalia: Microchiroptera), with special reference to species differences. 752 74

1. The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine. Its mechanism of action is unknown. We tested the effects of sodium valproate and GABAA-agonist muscimol on dural plasma protein ([125I]-bovine serum albumin) extravasation evoked by either unilateral trigeminal ganglion stimulation (0.6 mA, 5 ms, 5 Hz, 5 min) or substance P (SP) administration (1 nmol kg-1,i.v.) in anaesthetized Sprague-Dawley rats. 2. Intraperitoneal (i.p.) injection of sodium valproate or muscimol, but not baclofen (< or = 10 mg kg-1, i.p.) dose-dependently reduced dural plasma protein extravasation caused either by electrical trigeminal stimulation (ED50: 6.6 +/- 1.4 mg kg-1, i.p., and 58 +/- 18 micrograms kg-1, i.p. for valproate or muscimol, respectively) or by intravenous substance P administration (ED50: 3.2 +/- 1.4 mg kg-1, i.p. and 385 +/- 190 micrograms kg-1, i.p. for valproate or muscimol, respectively). 3. Valproate (6.6 mg kg-1, i.p.) or muscimol (58 micrograms kg-1, i.p.) had no effect on mean arterial blood pressure or heart rate when measured for 30 min after i.p. administration. 4. The GABAA-antagonist bicuculline (0.01 mg kg-1, i.p.) completely reversed the effect of valproate and muscimol on plasma extravasation following electrical stimulation or substance P administration, whereas the GABAB-receptor antagonist, phaclofen (0.01-1 mg kg-1, i.p.) did not. Bicuculline or phaclofen, given alone, did not alter the plasma extravasation response after either electrical stimulation or SP administration. 5. Valproate decreased plasma extravasation following substance P administration in adult animals, neonatally treated with capsaicin by a bicuculline-reversible mechanism. This suggests that GABAA receptors are not found primarily on those afferent neurones or fibres which are sensitive to capsaicin treatment in neonatal rats.6. We conclude that sodium valproate blocks plasma extravasation in the meninges through GABAA mediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinically. Agonists and modulators at the GABAA receptor may become useful for the development of selective therapeutic agents for migraine and cluster headache.
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PMID:Peripheral GABAA receptor-mediated effects of sodium valproate on dural plasma protein extravasation to substance P and trigeminal stimulation. 856 34

In addition to their potent vasoconstrictor properties, the endothelins (endothelin-1 and -3) may possess neurotransmitter/neuromediator and neuroendocrine actions. The aim of the present study was to evaluate the role of endothelins (ET) in mediating neurogenic inflammation of cephalic tissues in the rat. For this purpose, bosentan, a specific non-peptide mixed antagonist of ET receptors, was tested in rat models of neurogenic and non-neurogenic plasma extravasation in the dura mater and extracranial tissues (eyelid, conjunctiva, lip, tongue). Bosentan was effective for preventing neurogenic inflammation in the dura mater induced by unilateral electrical stimulation of the trigeminal ganglion or intravenous injection of capsaicin, whereas it was ineffective in extracranial tissues or after injection of substance P (non-neurogenic inflammation). The effect of nerve fiber stimulation on ET plasma concentrations in superior sagittal sinus was measured using selective radioimmunoassays for ET-1 and -3. Endothelin-3 concentration significantly increased after intravenous injection of capsaicin, whereas ET-1 levels remained unchanged. Competition binding assays on microsomal membranes from the trigeminal ganglion revealed a single class of binding sites with equal affinity for ET-1 and ET-3, suggesting a homogenous population of ETB receptors. The role of ETB receptors in mediating inflammation was evidenced by the lack of efficacy of a selective ETA receptor antagonist, in contrast to the full efficacy of a selective ETB receptor antagonist, for preventing neurogenic inflammation induced by unilateral stimulation of the trigeminal ganglion. The role of ETB receptors was finally confirmed by the observation that exogenous administration of the ETB receptor agonist sarafotoxin S6c also induced plasma protein extravasation in the dura mater. This extravasation was not a direct effect of ETB receptor stimulation, because it was inhibited by spantide, a selective tachykinin receptor antagonist. These data strongly suggest that ET, acting through ETB receptors, may play an important role in mediating neurogenic inflammation in the meninges of rats. Since the profile of activity of bosentan is similar to that of the 5-HT1D/B agonists, sumatriptan and ergot alkaloids, one may speculate that ET receptor antagonists might be potentially effective in the treatment of acute migraine attacks.
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PMID:Role of endothelin in mediating neurogenic plasma extravasation in rat dura mater. 874 Jun 9

1. The effects of progesterone, its A-ring-reduced metabolites, allopregnanolone, tetrahydroxydeoxycorticosterone and the synthetic neuroactive steroid alphaxalone were evaluated in a rat model of plasma extravasation within the meninges following unilateral electrical stimulation (ES) of the trigeminal ganglion (0.6 mA, 5 ms, 5 min) or substance P administration (1 nmol kg-1, i.v.). 2. When administered 55 min prior to electrical stimulation, progesterone (> or = 500 micrograms, s.c.) dose-dependently decreased plasma extravasation within the meninges (ED50: 650 micrograms) but not within conjunctiva and tongue. Promegestone (R5020), a non-metabolized progesterone agonist (1000 micrograms, i.p.) was ineffective. The administration of progestrone (> or = 500 micrograms s.c.) 55 min prior to substance P partially suppressed plasma extravasation within the meninges (ED50: 550 micrograms). 3. The GABAA-antagonist, bicuculline (ED50: 8.2 micrograms kg-1, i.p.) but not the GABAB-antagonist, phaclofen (100 micrograms kg-1, i.p.) attenuated the effects of progesterone after electrical stimulation and substance P administration. 4. The metabolites of progesterone, allopregnanolone (3 alpha-hydroxy-5 alpha- pregnan-20-one (THP); ED50: 0.58 micrograms kg-1, i.p.), tetrahydroxydeoxycorticosterone (3 alpha,21- dihydroxy-5 alpha-pregnan-20-one (THDOC); ED50: 1.2 micrograms kg-1, i.p.) as well as the synthetic steroid alphaxalone (3 alpha-hydroxy-5 alpha-pregnane-11,20-dione; ED50: 1.8 micrograms kg-1, i.p.) suppressed plasma extravasation dose-dependently following ES, whereas the epimer of allopregnanolone, 3 beta-hydroxy-5 alpha-pregnan-20-one (100 micrograms kg-1, i.p.), did not. Extravasation caused by SP administration was partially suppressed by allopregnanolone (> or = 1 microgram kg-1, i.p.) (ED50: 2.1 micrograms kg-1). 5. The effect of progesterone (1000 micrograms, s.c.) and allopregnanolone (100 micrograms kg-1, i.p.) on neurogenic plasma extravasation was reversed by bicuculline (10 micrograms kg-1, i.p.) or by a congener, bicuculline-methiodide (10 micrograms kg-1, i.p.) which does not cross the blood brain barrier. 6. Progesterone (1000 micrograms, s.c.) had no effect on mean arterial blood pressure or heart rate when measured for 60 min after administration. 7. These results indicate that neurosteroid modulation of a GABAA-receptor located outside the blood brain barrier suppresses neurogenic and substance P-induced plasma extravasation within the meninges. The findings are consistent with previously reported data showing that valproic acid and muscimol inhibit meningeal oedema by bicuculline-sensitive mechanisms. Drugs which activate GABAA-receptors and its modulatory sites might be clinically effective in the treatment of migraine and cluster headache.
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PMID:GABAA-receptor-mediated effects of progesterone, its ring-A-reduced metabolites and synthetic neuroactive steroids on neurogenic oedema in the rat meninges. 882 49

The localization of peptidergic, catecholaminergic, and nitroxidergic nerve fibers in the ventral leptomeningeal connective tissue compartment was studied in whole-mount preparations and serial semithin and ultrathin sections. For immunocytochemistry, whole-mount preparations of the leptomeninges and ventral brain slices with the meninges were incubated as free-floating specimens with primary antibodies against protein gene product 9.5 (PGP 9.5), substance P (SP), calcitonin gene-related peptide (CGRP), dopamine beta-hydroxylase (DbetaH), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), and nitric oxide synthase (NOS) using the avidin-biotin-peroxidase method. Based on the regional differences of the connective tissue organization, the leptomeninx is subdivided into the pial, trabecular, and adventitial leptomeninx. The antibody PGP 9.5 stains all unmyelinated nerve fibers in the leptomeninx. Although the highest density of nerve fibers occurs in the adventitial leptomeninx, nerve fibers, and terminals are additionally present in the trabecular and pial leptomeninx. DbetaH-, NPY-, VIP- and NOS-immunoreactive (IR) nerve fibers occur exclusively in the adventitial leptomeninx forming neuromuscular junctions. CGRP- and SP-IR nerve fibers are localized in all three leptomeningeal compartments where they terminate close to the subarachnoid space (type 1) or within the connective tissue (type 2). Due to their morphological and immunocytochemical characterization a possible chemo-, mechano- or nociceptive function is discussed in the context of pathophysiological aspects.
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PMID:Topography and immunocytochemical characterization of nerve fibers in the leptomeningeal compartments of the rat. A light- and electron-microscopical study. 901 85

1. The therapeutical benefit of serotonin (5-HT1) receptor agonists in the treatment of migraine headache has been attributed to their inhibitory effect on the release of pro-inflammatory neuropeptides from trigeminal afferents within the cranial meninges. The effect of 5-HT1 receptor agonists on the release of neuropeptides from central afferent terminals has not been examined so far. In the present study in the rat we therefore measured the effect of the 5-HT1B receptor agonist CP 93,129 on the stimulation-evoked release of immunoreactive substance P (ir-SP) in the spinal trigeminal nucleus. 2. To measure release of ir-SP, microprobes coated with antibody to substance P were inserted into the medulla oblongata at the level of the obex. The ipsilateral parietal dura mater encephali was exposed and stimulated with acid phosphate buffered Tyrode solution (pH 5.8). This chemical stimulus increased the release of ir-SP in the medullary dorsal horn. 3. Systemic (i.v.) administration of CP 93,129 (460 nmol kg(-1)) prior to stimulation suppressed the stimulation-evoked increase of release of ir-SP. Local administration of CP 93,129 (10 microM) to the dorsal surface of the medulla had no significant inhibitory effect on the release. 4. It is concluded that systemically applied 5-HT1 receptor agonists reduce the stimulation-evoked release of substance P from the central endings of meningeal afferents in the spinal trigeminal nucleus (medullary dorsal horn). This inhibitory effect may contribute to the antinociceptive effect of 5-HT1 receptor agonists in migraine.
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PMID:Release of immunoreactive substance P in the brain stem upon stimulation of the cranial dura mater with low pH - inhibition by the serotonin (5-HT1) receptor agonist CP 93,129. 988 64

The non-indole 5-HT receptor agonist, alniditan (R 91274), was tested and compared to sumatriptan in an in vivo model of neurogenic inflammation within the meninges of rats and in rat basilar artery in a Mulvany-Halpern chamber in vitro. Alniditan dose dependently attenuated the neurogenic inflammation and was more potent than sumatriptan. The alniditan response was blocked by the 5-HT(1B/D) receptor antagonist, GR 127935 (2'-methyl-4'-(5-methyl-[1,2, 4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide), but not by ketanserin, indicating that the effect is mediated through 5-HT(1B/D) receptors. Alniditan did not attenuate substance P-induced inflammation, suggesting that the mediating receptors are located prejunctionally. In vitro alniditan exhibited less vasoconstrictive effects on the rat basilar artery than did sumatriptan, although at a very high concentration (1 mM), alniditan caused intensive constriction, most likely through a mechanism independent from 5-HT receptor activation.
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PMID:Effects of alniditan on neurogenic oedema in the rat dura mater and on contraction of rat basilar artery. 1052 44


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