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 possible presynaptic action of the anti-migraine drug sumatriptan on primary afferent fibres containing substance P and/or calcitonin gene-related peptide was investigated on superfused rat horizontal spinal cord slices with attached dorsal roots. Electrical stimulation of dorsal roots triggered a significant overflow of both peptides; this could be reduced by sumatriptan in a concentration-dependent manner. As expected from the involvement of 5-HT1B/1.D beta receptors, methiothepin, (-)tertatolol and GR 127,935, but not WAY 100,635, prevented the inhibitors effect of sumatriptan. These data support the idea that the anti-migraine action of sumatriptan may involve, at least in part, a presynaptic inhibitory control of nociceptive (trigeminovascular) substance P- and/or calcitonin gene-related peptide-containing sensory fibres.
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PMID:Sumatriptan inhibits the release of CGRP and substance P from the rat spinal cord. 890 6

The role of substance P in the cerebral parenchymal circulation was examined in 19 anesthetized cats. The local cerebral blood volume in the temporoparietal cortex was measured by our photoelectric method. Cerebral blood volume reflects the cumulative dimensions of the parenchymal microvessels. Intravenous injection of 0.01, 0.1, and 1 mg/kg FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl) carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide) , a selective tachykinin NK1 receptor antagonist, had no significant effects (compared to the vehicle, ethanol) on cerebral blood volume and mean arterial blood pressure. Intracarotid injection of 1, 10, 100 pmol/kg, and 1 nmol/kg substance P increased cerebral blood volume (P < 0.01) in a dose-dependent manner (maximal increase of 6.5% at 5 min). Following injection of 1 nmol/kg substance P, cerebral blood volume was initially reduced, possibly due to the marked fall in mean arterial blood pressure (P < 0.01). The cerebral blood volume increase elicited by 1 nmol/kg substance P was strongly blocked (P < 0.05) by prior injection of 1 mg/kg FK888. However, the depressor effect of 1 nmol/kg substance P (-24 +/- 4 mm Hg at 30 s, P < 0.01) was partially inhibited (P < 0.01) by FK888. We conclude that endogenous substance P may not have a significant role in the maintenance of resting tone of cerebral parenchymal vessels. Intravascular substance P, however, dilates the small microvessels through a specific tachykinin NK1 receptor and could be involved in the development of pathologic processes such as migraine headache.
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PMID:Intravascular substance P dilates cerebral parenchymal vessels through a specific tachykinin NK1 receptor in cats. 899 10

Long-acting somatostatin analogue (SMS 201-995) inhibits serotonin, bradykinin, prostaglandins, substance P, and vasoactive intestinal peptide, which may be involved in migraine. We therefore decided to test the efficacy of SMS 201-995 in relieving the pain of acute migraine attacks. Headache relief was defined as a reduction in severity from grade 3 or 2 (severe or moderate) to 1 or 0 (mild or none). Patients experiencing migraine attacks were evaluated clinically. A double-blind parallel group trial was performed in which patients randomly received either a subcutaneous injection of placebo (saline) or SMS 201-995 (100 micrograms). SMS 201-995 was significantly more effective than placebo in reducing headache grade at 2 h (1.5 +/- 0.6 vs 2.2 +/- 0.7; p < 0.01), 4 h (1.5 +/- 0.6 vs 2.1 +/- 0.8; p < 0.05) and 6 h (0.8 +/- 0.9 vs 2.1 +/- 0.8; p < 0.001) after the initiation of treatment. By 6 h, apparent headache relief (reduction in severity from grade 3 or 2 to 1 or 0) was experienced in 76.5% of SMS 201-995 treated patients and 25% of the placebo-treated group. Headache relief was significantly better in patients taking SMS 201-995 (p < 0.02). Furthermore, none of the patients became pain-free (headache grade 0) on placebo, while significantly more patients (47%) were pain-free on SMS 201-995 at 6 h (p < 0.01). Headache improvement started significantly earlier in those patients treated with SMS 201-995 than with placebo. SMS 201-995 significantly improves the pain of migraine attacks, 2 h after the beginning of treatment. Additionally, we observed no side effects of SMS 201-995. We therefore conclude that a single dose of 100 micrograms given subcutaneously is an effective and well-tolerated agent for the treatment of migraine attacks.
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PMID:Treatment of migraine attacks with a long-acting somatostatin analogue (octreotide, SMS 201-995). 905 32

The in vivo activity of GR205171, a novel, highly potent non-peptide tachykinin NK1 receptor antagonist, has been investigated in the trigeminovascular system in order to assess its potential as an acute therapy for migraine headache. In anaesthetised rabbits, GR205171 attenuated reductions in carotid arterial vascular resistance evoked by the tachykinin NK1 receptor agonist, substance P methyl ester (SPOMe), injected via the lingual artery (DR30 (i.e., the dose producing a dose-ratio of 30) = 0.4 microgram/kg, i.v.). In anaesthetised rats, GR205171 (0.1 and 1 mg/kg, i.v.) produced a dose-dependent inhibition of plasma protein extravasation (PPE) in dura mater, conjunctiva, eyelid and lip in response to electrical stimulation of the trigeminal ganglion. In anaesthetised guinea-pigs, GR205171 (1.10 and 100 micrograms/kg, i.v.) inhibited, by up to approximately 60%, expression of c-fos in the trigeminal nucleus caudalis in response to electrical stimulation of the trigeminal ganglion. It is concluded that GR205171 is a potent antagonist of NK1 receptor-mediated cranial vasodilatation, dural PPE and expression of c-fos in the trigeminal nucleus caudalis. Such a profile of action suggests that GR205171 may have potential as a novel therapeutic agent in the treatment of migraine headache.
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PMID:The activity of GR205171, a potent non-peptide tachykinin NK1 receptor antagonist, in the trigeminovascular system. 909 51

LY303870 is a competitive, high affinity NK-1 receptor antagonist. It was tested in the trigeminal stimulation-induced neurogenic dural inflammation model of migraine. The neurogenic inflammation theory of migraine pain proposes that substance P, acting through NK-1 receptors, causes dural inflammation which enhances migraine pain. LY303870 administration potently inhibited neurogenic dural inflammation as measured by plasma protein extravasation caused by electrical stimulation of the trigeminal ganglion in guinea pigs. It was active in this model when administered via intravenous, oral or inhalation routes. LY306155, the enantiomer of LY303870 with lower affinity for the NK-1 receptor, was much less potent than LY303870 in this model. LY303870, at oral doses of 1, 10 and 100 microg/kg, produced a long, dose-dependent inhibition of dural inflammation, demonstrating a suitable duration of action for a potential use in acute migraine and migraine prophylaxis.
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PMID:The non-peptide NK-1 receptor antagonist LY303870 inhibits neurogenic dural inflammation in guinea pigs. 912 77

These studies in anaesthetised rats showed, using intravital microscopy, that the novel anti-migraine agent, rizatriptan, significantly reduced electrically stimulated dural vasodilation but had no effect on increases in dural vessel diameter produced by exogenous substance P or calcitonin gene-related peptide (CGRP). Rizatriptan also significantly inhibited dural plasma protein extravasation produced by high intensity electrical stimulation of the trigeminal ganglion. We suggest that rizatriptan inhibits the release of sensory neuropeptides from perivascular trigeminal nerves to prevent neurogenic vasodilation and extravasation in the dura mater. These prejunctional inhibitory effects may be involved in the anti-migraine action of rizatriptan.
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PMID:The novel anti-migraine agent rizatriptan inhibits neurogenic dural vasodilation and extravasation. 920 69

This study describes a novel intravital microscope technique for direct measurement of dural blood vessel diameter through a closed cranial window in anaesthetized rats. This technique avoids removal of the skull, which can lead to problems of altered vessel reactivity and brain swelling that are encountered with open cranial window techniques. Substance P and calcitonin gene-related (CGRP) evoked increases in dural vessel diameter, which were abolished by the NK1 receptor antagonist, RP67580 and the CGRP receptor antagonist, human-alpha CGRP(8-37) respectively. Neurokinin A produced increases in dural vessel diameter which were unaffected by the NK2 receptor antagonist SR 48968 but were blocked by RP67580, suggesting that neurokinin A can act through NK1 receptors to produce dural vasodilation in rats. The NK3 receptor agonist, senktide, had no effects on dural vessel diameter. All drugs were administered intravenously. In humans, vasodilation within the meningeal vasculature has been implicated in the pathogenesis of migraine, the present experiments indicate that substance P or neurokinin A (both acting through NK1 receptors) or CGRP may be responsible.
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PMID:Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural vessel diameter in the anaesthetized rat. 920 73

In 1996, our knowledge of acute antimigraine therapy expanded in three major areas. First, large surveys have confirmed the remarkable efficacy profile of sumatriptan in clinical practice. No satisfying clinical, pharmacokinetic or genetic explanations were found for its major shortcomings: nonresponders, headache recurrence and noncardiac chest symptoms. Second, the novel 5-HT1B/D agonists zolmitriptan (311C90), rizatriptan (MK-462), eletriptan (UK-116,044), avitriptan (BMS-180048) and alniditan (R091274) were all proved superior to placebo for attack treatment, but their advantages over sumatriptan are yet to be analysed in more detail. A higher lipophilicity explains (except for alniditan) their greater oral bioavailability and better central nervous system penetration. A central action now proved experimentally in animals and in humans for 5-HT1B/D agonists such as zolmitriptan may be advantageous for the antimigraine efficacy, but it could also increase sedation. Third, an endothelin (Ro470203, bosentan) and a neurokinin 1 (RPR100893) receptor antagonist were found to be ineffective in migraine. Both compounds are potent inhibitors of neurogenic plasma extravasation in rat dura mater, which might suggest that this pharmacological property does not necessarily predict efficacy in aborting migraine attacks.
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PMID:Acute migraine therapy: the newer drugs. 922 32

Migraine is a common and disabling disease of uncertain pathogenesis. Research on the trigeminovascular system, serotonin receptors, and substance P have provided clues to improving the pharmacotherapy of this disorder. Selective serotonin agonists, such as sumatriptan, dihydroergotamine, ergotamine tartrate, nonsteroidal anti-inflammatory drugs (NSAIDS), isometheptene mucate, and phenothiazines are useful to treat acute attacks. Prophylactic agents include beta-blockers, calcium channel blockers, NSAIDs, antidepressants, and valproate. The addition of several new agents for the acute and prophylactic therapy of migraine has improved the outlook for this debilitating disorder.
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PMID:The pharmacology of medications used in treating headache. 942 44

To investigate the possible role of 5HT1B and/or 5HT1D receptors in controlling neurogenic inflammation, we performed a co-localization study of the mRNA for 5HT1B and 5HT1D receptors and of substance P or calcitonin gene-related peptide (CGRP) mRNA in the guinea pig trigeminal ganglion using double labelling in situ hybridization techniques. The 5HT1D receptor mRNA is abundant whereas 5HT1B receptor mRNA is scarce. The vast majority of cells containing substance P mRNA also contained 5HT1B receptor mRNA, but very few cells expressed substance P mRNA and 5HT1D receptor mRNA. Both receptor mRNAs were co-localized with CGRP mRNA. Hence, 5HT1D receptors may control the release of CGRP only, whereas 5HT1B receptors may control the release of both substance P and CGRP. The question remains whether selective 5HT1D agonists will have migraine abortive properties.
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PMID:5HT1B and 5HT1D receptor mRNA differential co-localization with peptide mRNA in the guinea pig trigeminal ganglion. 955 31


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