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

Clinical and experimental evidence suggest, that migraine reflects a biological disorder of the brain. On the basis of a genetic predisposition, variations in internal rhythms may change the responsiveness towards external trigger factors. During the migraine attack changes occur in the cortical neuronal activity, in cerebral blood flow and in the activity of neuropeptide neurotransmitters such as substance P and calcitonin-gene-related-peptide. The consequence is an aseptic inflammation in the wall of dural arteries. Sumatriptan is a new agent which selectively acts at 5-HT-1D receptors in brain vessels and improves headache and autonomic symptoms in severe migraine attacks. Sumatriptan is also helpful in the treatment of headache attacks in cluster headache. The treatment of chronic tension-type headache requires the combination of tricyclics with behavioral techniques such as relaxation training.
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PMID:[Headache--what is the current status?]. 819 78

CP-122,288 and CP-122,638 blocked plasma protein extravasation response within dura mater following trigeminal ganglion stimulation. The threshold (1 and 0.1 pmol/kg, respectively) was remarkably lower than for sumatriptan (7 nmol/kg), as was the dose at maximum response. As with sumatriptan, substance P-induced plasma leakage was unaffected by either compound, and metergoline only partially (27%) reversed the effects of CP-122,288. The data suggest the importance of modifications at the aminoethyl side chain to the actions of sumatriptan and possibly to the treatment of migraine headache.
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PMID:Conformationally restricted sumatriptan analogues, CP-122,288 and CP-122,638 exhibit enhanced potency against neurogenic inflammation in dura mater. 828 39

Monocyte chemotactic and phagocytic responses were assessed in two groups of migraine patients (with and without aura) and in two groups of tension-type headache patients (episodic and chronic). The chemotactic but not the phagocytic response, assessed interictally, is significantly lower in migraine patients (p < 0.006) and in episodic tension-type headache patients, though not so significantly in the latter (p < 0.05), than in the control individuals. The chemotactic response tends to increase significantly during attack in migraine patients both with and without aura (p < 0.008 and p < 0.007 respectively). The same was evident for the phagocytic response in both migraine patient groups (p < 0.007 and 0.0004). No modifications of monocyte functions were found during attacks neither in episodic nor chronic tension-type headache patients. These findings suggest that one or more mediators of neurogenic inflammation having phagocytic and chemotactic enhancing properties (substance P, prostaglandin E and thromboxane A2 etc.) are implicated in the modification of monocyte function. The demonstration of a defect in monocyte function during the interictal period in migraine patients confirms the results of recent research which evidenced reduced capacity of monocyte to phagocyte and kill microorganisms in the course of migraine.
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PMID:Monocyte chemotactic and phagocytic responses in migraine and tension-type headache patients. 850 70

We measured, by RIA methods, ictal and interictal levels of substance P (SP), calcitonin-gene related peptide (CGRP) and neurokinin A (NKA) in the plasma of 30 young migraine patients with aura (MPA) and 45 migraine patients without aura (MWA), and compared the results with those of 30 age-matched controls. There were no significant differences between the levels of these vasoactive peptides in the control group and the levels in both migraine groups studied in headache-free periods. An elevation of CGRP levels in plasma was found during attacks in MPA and, to a lesser extent, in MWA (p < 0.03 and p < 0.05, respectively). A significant increase in NKA levels was also demonstrated in the MPA and MWA groups (p < 0.02 and p < 0.04, respectively). These data suggest, although indirectly, that CGRP and NKA could be involved in the pathogenesis of migraine attacks in juvenile migraine patients.
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PMID:Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. 853 90

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

1. The in vitro and in vivo pharmacology of GR203040 ((2S, 3S)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), a novel, highly potent and selective non-peptide tachykinin NK1 receptor antagonist, was investigated in the present study. 2. GR203040 potently inhibited [3H]-substance P binding to human NK1 receptors expressed in Chinese hamster ovary (CHO) and U373 MG astrocytoma cells, and NK1 receptors in ferret and gerbil cortex (pKi values of 10.3, 10.5, 10.1 and 10.1 respectively). GR203040 had lower affinity at rat NK1 receptors (pKi = 8.6) and little affinity for human NK2 receptors (pKi < 5.0) in CHO cells and NK3 receptors in guinea-pig cortex (pKi < 6.0). With the exception of the histamine H1 receptor (pIC50 = 7.5). GR203040 had little affinity (pIC50 < 6.0) at all non-NK1 receptors and ion channels examined. Furthermore, GR203040 produced only weak inhibition of Na+ currents in SH-SY5Y neuroblastoma and superior cervical ganglion cells (pIC50 values < 4.0). GR203040 produced only weak antagonism of Ca(2+)-evoked contractions of rat isolated portal vein (pKn = 4.1). The enantiomer of GR203040, GR205608 (2R, 3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), had 10,000 fold lower affinity at the human NK1 receptor expressed in CHO cells (pKi = 6.3). 3. In gerbil ex vivo binding experiments, GR203040 produced a dose-dependent inhibition of the binding of [3H]-substance P to cerebral cortical membranes (ED50 = 15 micrograms kg-1 s.c. and 0.42 mg kg-1 p.o.). At 10 micrograms kg-1 s.c., the inhibition of [3H]-substance P binding was maintained for > 6 h. In the rat, GR203040 was less potent (ED50 = 15.4 mg kg-1 s.c.) probably reflecting, at least in part, its lower affinity at the rat NK1 receptor. 4. In guinea-pig isolated ileum and dog isolated middle cerebral and basilar arteries, GR203040 produced a rightward displacement of the concentration-effect curves to substance P methyl ester (SPOMe) with suppression of the maximum agonist response (apparent pKB values of 11.9, 11.2 and 11.1 respectively). 5. In anaesthetized rabbits, GR203040 antagonized reductions in carotid arterial vascular resistance evoked by SPOMe, injected via the lingual artery (DR10 (i.e. the dose producing a dose-ratio of 10) = 1.1 micrograms kg-1, i.v.). At a dose 20 fold greater than its DR10 value (i.e. 22 micrograms kg-1, i.v.), significant antagonism was evident more than 2 h after GR203040 administration. 6. In anaesthetized rats, GR203040 (3 and 10 mg kg-1, i.v.) produced a dose-dependent inhibition of plasma protein extravasation in dura mater, conjunctiva, eyelid and lip in response to electrical stimulation of the trigeminal ganglion. 7. It is concluded that GR203040 is one of the most potent and selective NK1 receptor antagonists yet described, and as such, has considerable potential as a pharmacological tool to characterize the physiological and pathological roles of substance P and NK1 receptors. GR203040 may also have potential as a novel therapeutic agent for the treatment of conditions such as migraine, emesis and pain.
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PMID:The pharmacology of GR203040, a novel, potent and selective non-peptide tachykinin NK1 receptor antagonist. 871 89

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

Substance P, 5-hydroxytryptamine, and gamma-aminobutyric acid levels in saliva were measured in 55 patients with migraine during headache attacks (15 men and 40 women, average age 37.6 years), 36 patients with migraine in interictal periods (8 men and 28 women, average age 43.9 years), 48 patients with tension-type headache during headache attacks (18 men and 30 women, average age 47.3 years), and 25 patients with tension-type headache in interictal periods (10 men and 15 women, average age 48.6 years). Forty-three normal healthy volunteers composed the control group (17 men and 26 women, average age 32.7 years). Substance P levels in saliva were determined using competitive enzyme-linked immunosorbent assay, and were 26.9 +/- 45.1 pmol/mL in the patients with migraine during headache attacks, 30.0 +/- 59.7 pmol/mL in the patients with migraine in interictal periods, 243.5 +/- 1137 pmol/mL in the patients with tension-type headache during headache attacks, 101.3 +/- 364 pmol/mL in the patients with tension-type headache in interictal periods, and 21.2 +/- 17.4 pmol/mL in the healthy controls. 5-hydroxytryptamine levels in saliva were determined using reversed-phase high-performance liquid chromatography with electrochemical detection, and were 895 +/- 1075 ng/mL in the patients with migraine during headache attacks, 758 +/- 1375 ng/mL in the patients with migraine in interictal periods, 1646 +/- 1945 ng/mL in the patients with tension-type headache during active headache periods, 1167 +/- 1495 ng/mL in the patients with tension-type in headache-free periods, and 450 +/- 405 ng/mL in the healthy controls. Gamma-aminobutyric acid levels in saliva were determined using high-performance liquid chromatography with precolumn ortho-phthalaldehyde fluorescence detection. Gamma-aminobutyric acid levels in saliva were 36.8 +/- 49.8 pmol/mL in the patients with migraine during headache attacks, 17.9 +/- 25.2 pmol/mL in the patients with migraine in interictal periods, 16.0 +/- 18.3 pmol/mL in the patients with tension-type headache during active headache periods, 14.1 +/- 6.8 pmol/mL in the patients with tension-type headache in headache-free periods, and 21.6 +/- 22.7 pmol/mL in the healthy controls. The salivary substance P and 5-hydroxytryptamine levels in the patients with tension-type headache during active headache periods were significantly higher than those in healthy controls. In contrast, we found no significant differences between the salivary gamma-aminobutyric acid levels in the patients with tension-type headache and healthy controls. The high levels of salivary substance P and 5-hydroxytryptamine in tension-type headache patients during headache periods might reflect release of substance P from the pain sensory system. Saliva could represent a fluid particularly suitable to the study of neuropeptide release under specific conditions such as migraine and tension-type headache.
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PMID:Salivary substance P, 5-hydroxytryptamine, and gamma-aminobutyric acid levels in migraine and tension-type headache. 874 82

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 role of substance P and the influence of neurokinin 1 (NK1) receptor antagonists in the cranial circulation are described in the present review, particularly with respect to the mechanisms involved in the etiology of migraine headache. Substance P is distributed throughout the cranial vasculature, in the trigeminal sensory afferent nerve fibres, and its release can be demonstrated following activation of the trigeminovascular system in animals and humans. Following its release and NK1 receptor activation, dilatation and edema result, two events that are implicated in the pathogenesis of migraine headache. The recently developed selective NK1 receptor antagonists inhibit substance P mediated dilatation and plasma protein extravasation in the cranial circulation, suggesting that they may provide an effective and novel acute treatment for migraine.
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PMID:Recent developments in tachykinin NK1 receptor antagonists: prospects for the treatment of migraine headache. 884 24


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