UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A role for serotonin in migraine has been supported by changes in circulating levels of serotonin and its metabolites during the phases of a migraine attack, along with the ability of serotonin-releasing agents to induce migraine-like symptoms. The development of serotonin receptor agonists with efficacy in the clinic for the alleviation of migraine pain further implicates serotonin as a key molecule in migraine. Several theories regarding the etiology of migraine have been proposed. The vasodilatory theory of migraine suggested that extracranial arterial dilation during an attack was related to migraine pain; a theory supported when vasoconstrictors such as sumatriptan alleviated migraine pain. The neurological theory of migraine proposed that migraine resulted from abnormal firing in brain neurons. Cortical spreading depression, one facet of the neurological theory, could explain the prodrome of migraine. The neurogenic dural inflammation theory of migraine supposed that the dural membrane surrounding the brain became inflamed and hypersensitive due to release of neuropeptides from primary sensory nerve terminals. Substance P, calcitonin gene related peptide and nitric oxide are all though to play a role in the dural inflammatory cascade. Animal models of migraine have been utilized to study the physiology of migraine and develop new pharmaceutical therapies. One model measures the shunting of blood to arteriovenous anastomoses based on a proposal that migraine primarily involves cranial arteriovenous vasodilation. Another model utilizes electrical stimulation of the trigeminal ganglion to induce neurogenic dural inflammation quantified by the resulting extravasation of proteins. Pharmacological agents such as meta-chlorophenylpiperazine (mCPP) and nitroglycerin have also been used to induce dural extravasation in animals. Both compounds also induce migraine attacks in individuals with a history of migraine. In addition, Fos, a protein produced by activation of the c-fos gene, has been measured as an index of migraine-like pain transmission to the CNS following chemical or electrical stimulation of the trigeminal nerve. A role for serotonin in migraine is further supported by the efficacy of serotonin receptor ligands. Sumatriptan is an agonist at 5-HT1D and 5-HT1B receptor subtypes, and effective in treating migraine pain and associated symptoms. Recently, selective 5-HT1F agonists have been proposed for the treatment of migraine, without the side effects associated with the present 5-HT1D and 5-HT1B receptor agonists. A role for 5-HT2B receptors has also been suggested the initiation of migraine, supporting use of selective 5-HT2B receptor antagonists in migraine. Thus, agents that modulate 5-HT1B, 5-HT1D, 5-HT1F and 5-HT2B receptors either have or may have clinical utility in the therapy of migraine headache.
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PMID:Serotonin in migraine: theories, animal models and emerging therapies. 994 63

The respiratory response to microinjection of substance P (SP) into the commissural nucleus of the solitary tract (cNTS) and binding of [125I]-Bolton-Hunter SP ([125I]-BHSP) to brain stem NK1 receptors were compared in young and aged rats. Injection of SP (750 pmol) into the cNTS of young rats (2 months) increased tidal volume (VT) but had no effect on respiratory rate (f). In aged rats (19-21 months), injection of SP had no significant effect on f or VT. The NTS of aged rats displayed significantly lower specific [125I]-BHSP binding than young rats, indicating a reduction in the number in NK1 receptors. These findings show that the respiratory response to microinjection of SP into the cNTS of aged rats is severely blunted and that this phenomenon may be due to a decrease in the number of NK1 receptors in the NTS.
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PMID:Altered respiratory response to substance P and reduced NK1 receptor binding in the nucleus of the solitary tract of aged rats. 1021 6

1. The respiratory response to microinjection of capsaicin and tachykinin receptor agonists into the commissural nucleus of the solitary tract (cNTS) was investigated in adult, urethane-anaesthetized rats which had been pretreated with capsaicin (50 mg kg(-1) s.c.) or vehicle (10% Tween 80, 10% ethanol in saline) as day 2 neonates. 2. Microinjection of capsaicin (1 nmol) into the cNTS of vehicle-pretreated rats, significantly reduced respiratory frequency (59 breaths min(-1), preinjection control, 106 breaths min(-1)) without affecting tidal volume (VT). In capsaicin-pretreated rats, the capsaicin-induced bradypnoea was markedly attenuated (minimum frequency, 88 breaths min(-1); control, 106 breaths min(-1)). 3. In vehicle-pretreated rats, microinjection of substance P (SP, 33 pmol), neurokinin A (NKA, 33 pmol) and NKB (330 pmol), and the selective NK(1) tachykinin receptor agonists, [Sar(9), Met(O(2))(11)]-SP (33 pmol) and septide (10 pmol), increased VT (maxima, 3.60 - 3.93 ml kg(-1)) compared with preinjection control (2.82 ml kg(-1)), without affecting frequency. The selective NK(3) agonist senktide (10 pmol) also increased VT (3.93 ml kg(-1)) which was accompanied by a bradypnoea (-25 breaths min(-1)). The selective NK(2) agonist, [Nle(10)]-NKA(4-10) (330 pmol) increased VT slightly but significantly decreased frequency (-12 breaths min(-1)). In capsaicin-pretreated rats, VT responses to SP and [Sar(9), Met(O(2))(11)]-SP were increased whereas the response to septide was abolished. Both the VT and bradypnoeic responses to senktide and [Nle(10)]-NKA(4-10) were significantly enhanced. 4. These results show that neonatal capsaicin administration markedly reduces the respiratory response to microinjection of capsaicin into the cNTS. The destruction of capsaicin-sensitive afferents appears to sensitize the NTS to SP, NKB, [Sar(9),Met(O(2))(11)]-SP, senktide and [Nle(10)]-NKA(4-10). Moreover, the loss of septide responsiveness in capsaicin-pretreated rats, suggests that 'septide-sensitive' NK(1) receptors may be located on the central terminals of afferent neurons.
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PMID:Respiratory actions of tachykinins in the nucleus of the solitary tract: effect of neonatal capsaicin pretreatment. 1072 61

Formation of oxidized phosphatidylcholine (ox-PC), oxidatively fragmented phosphatidylcholine (PC) containing a short-chain and/or polar oxidative residue at the sn-2 position, in the process of LDL oxidation as well as its existence in atherosclerotic lesions has been demonstrated. To clarify the pathophysiological role of ox-PC in the vascular reactivity, we investigated the effects of various ox-PCs on the isometric tensions in rabbit thoracic aortas. Ox-PCs, which were produced upon oxidation of sn-2 polyunsaturated fatty acid (PUFA)-containing PCs, dose-dependently inhibited endothelium-dependent relaxation (EDR) evoked by acetylcholine or substance P. On the other hand, neither native PUFA-containing PCs nor an oxidative product of monounsaturated fatty acid-containing PC showed an inhibitory effect. None of ox-PCs affected endothelium-independent relaxation to nitroglycerin. The PC-headgroup fraction, but not the oxidized fatty acids fraction, was responsible for the inhibition of EDR by ox-PC. EDR was reduced by 2-(5-oxovaleroyl)-PC, one of the secondary oxidative products of PCs that contains a short chain aldehydic residue at the sn-2 position, but not by PC hydroperoxide, the primary oxidative product. Although the possibility could not be completely ruled out that lysophosphatidylcholine rather than ox-PC may be responsible for inhibitory effects on EDR, these results suggest a novel vascular activity of ox-PCs generated from sn-2 PUFA-containing PCs which may be implicated in the pathophysiology of vascular tone.
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PMID:Inhibition of endothelium-dependent arterial relaxation by oxidized phosphatidylcholine. 1099 42

Despite evidence emerging from the experimental model of nitroglycerin-induced headache, the endogenous increase in nitric oxide (NO) production during migraine attacks is only speculative. It has been hypothesized that there is a close relationship between activation of the L-arginine/NO pathway and production of certain vasoactive and algogenic prostaglandins during spontaneous migraine attacks, but this suggestion also needs to be confirmed. In the present study the levels of nitrites, the stable metabolites of NO, were determined with high performance liquid chromatography (HPLC) in the internal jugular venous blood of five patients affected by migraine without aura examined ictally. These samples were taken within 30 min, 1, 2, and 4 h from the onset of the attack and at the end of the ictal period. At the same time, the plasma levels of calcitonin gene-related peptide (CGRP), neurokinin A (NKA), prostaglandin E2 (PGE2) and 6 keto PGF1alpha, the stable product of PGI2, were assessed with radioimmunoassay (RIA) kits in the same samples. The levels of the intracellular messengers, cGMP and cAMP, were also measured with the RIA method. Nitrite, cGMP, CGRP and NKA levels reached their highest values at the first hour, then they tended to decrease progressively and returned, after the end of attacks, to values similar or below those detected at the time of catheter insertion (ANOVA, statistical significance: P<0.001; P<<0.002; P<0.002; P<0.003, respectively). PGE2 and 6 keto PGF1alpha, as well as cAMP levels also significantly increased at the first hour but reached a peak at the 2nd hour and remained in the same range until the 4th and 6th hours. Then their values tended to decrease after the end of attacks, becoming lower than those measured immediately after catheter positioning for internal jugular venous blood drawing (ANOVA: P<0.002, P<0.004, P<0.001, respectively). Our results support early activation of the L-arginine/NO pathway which accompanies the release of vasoactive peptides from trigeminal endings and a late rise in the synthesis of prostanoids with algogenic and vasoactive properties which may intervene in maintaining the headache phase.
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PMID:Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. 1130 26

Chronic administration of erythropoietin (EPO) is often associated with hypertension in animals and humans. The aim of this study was to estimate whether 1-week treatment with EPO can affect the vascular endothelial function. Rabbits were given with EPO (400 iu kg(-1) s.c.) or saline each other day for 1 week. Hypotensive responses to intravenously given acetylcholine (ACh), endothelium-independent nitric oxide donors (NOC7, nitroprusside and nitroglycerin) and prostaglandin I2 were tested before and after administration of N(G)-nitro-L-arginine methyl ester (L-NAME), a specific nitric oxide synthase inhibitor, under pentobarbitone anaesthesia. Blood haemoglobin concentration in EPO group was significantly higher than that in control group, whereas baseline values of aortic pressure, heart rate and femoral vascular resistance were similar. The dose of ACh (172 ng kg(-1)) requiring for a 15 mmHg hypotension from the baseline in EPO group was apparently higher than that (55 ng kg(-1)) in control group. On the contrary, hypotensive responses to NOC7, nitroprusside, nitroglycerin and prostaglandin I2 were comparable between two groups. The extent of ACh-induced hypotension did not correlate with haemoglobin concentration. L-NAME significantly inhibited the ACh-induced vasodilating response in control group but did not in EPO group. In another set of rabbits, the same treatment with EPO also decreased vasodilating responses to carbachol, bradykinin and substance P besides ACh as compared with control group. These results indicate that 1-week treatment with EPO selectively attenuates depressor responses to endothelium-dependent vasodilators in anaesthetized rabbits, most likely due to inhibition of endothelial nitric oxide synthase.
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PMID:Effect of 1-week treatment with erythropoietin on the vascular endothelial function in anaesthetized rabbits. 1137 56

Isometric muscle contractions cause an increase in mean arterial pressure and heart rate. Previously, we showed that substance P (SP) is released from sites in the feline medial nucleus tractus solitarius (mNTS) in response to isometric muscle contractions, and that it most likely interacted with NK(1) tachykinin receptors at these sites. This study was undertaken to determine whether other tachykinin receptors in this area of the brainstem are involved with the muscle pressor response. Receptor autoradiography, using [(125)I]Bolton-Hunter SP and [(125)I] [MePhe(7)] neurokinin B to label NK(1) and NK(3) receptors, respectively, indicated that NK(3) tachykinin receptors are as abundant as NK(1) and NK(3) receptors, respectively, indicated that NK(3) tachykinin receptors are as abundant as NK(1) receptors in this region of the feline brainstem Injections of the specific NK(3) receptor antagonist, SR 142801 (0.1 to 10 microM) into the mNTS did not modify the pressor response or the heart rate response to isometric muscle contractions. Injection of SR142801 into the NTS prior to the injection of the NK(1) antagonist, GR82334 did not affect the action of GR82334 to attenuate the muscle pressor reflex. We conclude that NK(3) receptors in the NTS are not involved with the regulation of cardiovascular function during activation of the muscle pressor response.
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PMID:NK(3) receptors in the feline nucleus tractus solitarius are not involved with the muscle pressor response. 1188 5

Calcitonin gene-related peptide (CGRP) and substance P (SP) play an important role in the development of pain and hyperalgesia. Experimental models have demonstrated that nitroglycerin (NTG)--a nitric oxide donor--provokes a hyperalgesic state, probably via the activation of second-order neurons in the nucleus trigeminalis caudalis. In order to gain further insight into the role of CGRP and SP in different types of experimental pain, we evaluated and compared changes in immunoreactivity (-ir) for these two neuropeptides at different levels of the central nervous system [nucleus trigeminalis caudalis (NTC) and dorsal horns of the lumbar spinal cord] in two animal models of hyperalgesia: systemic NTG administration and formalin test. Following NTG administration, CGRP-ir decreased steadily in the NTC, whereas SP-ir increased transiently. In the lumbar dorsal horns, NTG induced a decrease in SP-ir 1 h after its administration. Formalin injection induced an ipsilateral increase in both CGRP and SP immunostaining at 1 and 2 h in the lumbar dorsal horns. In the NTC, a significant decrease in CGRP-ir was observed at 1 h. The changes in the staining intensities were paralleled by changes in the numbers of CGRP and of SP varicosities in both the NTC and the lumbar dorsal horns. These findings show specific changes in CGRP and SP at different levels of the central nervous system in the different models of pain. In the case of the formalin test, the changes involve both neuropeptides synchronously and to the same extent, whereas in the case of NTG administration, CGRP seems to play a more prevalent and long-lasting role, particularly at the NTC level.
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PMID:Role of calcitonin gene-related peptide and substance P in different models of pain. 1819 82

Cisplatin chemotherapy frequently causes severe vomiting in two temporally separated clusters of bouts dubbed the acute and delayed phases. Cannabinoids can inhibit the acute phase, albeit through a poorly understood mechanism. We examined the substrates of cannabinoid-mediated inhibition of both the emetic phases via immunolabeling for serotonin, Substance P, cannabinoid receptors 1 and 2 (CB(1), CB(2)), and the neuronal activation marker Fos in the least shrew (Cryptotis parva). Shrews were injected with cisplatin (10mg/kg i.p.), and one of vehicle, Delta(9)-THC, or both Delta(9)-THC and the CB(1) receptor antagonist SR141716A (2mg/kg i.p.), and monitored for vomiting. Delta(9)-THC-pretreatment caused concurrent decreases in the number of shrews expressing vomiting and Fos-immunoreactivity (Fos-IR), effects which were blocked by SR141716A-pretreatment. Acute phase vomiting induced Fos-IR in the solitary tract nucleus (NTS), dorsal motor nucleus of the vagus (DMNX), and area postrema (AP), whereas in the delayed phase Fos-IR was not induced in the AP at all, and was induced at lower levels in the other nuclei when compared to the acute phase. CB(1) receptor-IR in the NTS was dense, punctate labeling indicative of presynaptic elements, which surrounded Fos-expressing NTS neurons. CB(2) receptor-IR was not found in neuronal elements, but in vascular-appearing structures. All areas correlated with serotonin- and Substance P-IR. These results support published acute phase data in other species, and are the first describing Fos-IR following delayed phase emesis. The data suggest overlapping but separate mechanisms are invoked for each phase, which are sensitive to antiemetic effects of Delta(9)-THC mediated by CB(1) receptors.
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PMID:Delta 9-tetrahydrocannabinol suppresses vomiting behavior and Fos expression in both acute and delayed phases of cisplatin-induced emesis in the least shrew. 1872 29

The present study utilized a nitroglycerin-induced rat model of migraine to detect the effects of rizatriptan benzoate on proenkephalin and substance P gene expression in the midbrain using real-time quantitative polymerase chain reaction and investigate whether rizatriptan benzoate can regulate the endogenous pain modulatory system. The results showed that rizatriptan benzoate significantly reduced expression of the mRNAs for proenkephalin and substance P. Rizatriptan benzoate may inhibit the analgesic effect of the endogenous pain modulatory system.
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PMID:Rizatriptan benzoate influences the endogenous pain modulatory system in a rat model of migraine. 2576 88

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