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)

Intravenous administration of an alpha-adrenoceptor agonist, UK-14,304, a histamine H3 receptor agonist, R(-)-alpha-methyl-histamine (alpha-MeHA) or SMS 201-995 (a synthetic octapeptide analogue of somatostatin), blocked plasma protein (125I-albumin) extravasation within rat and/or guinea pig dura mater following unilateral electrical trigeminal ganglion stimulation or capsaicin administration. The extravasation caused by the administration of the neuropeptide mediator, substance P, was not inhibited by any of the three compounds. Blockade by UK-14,304 was completely antagonized by pretreatment with the highly selective alpha 2-antagonist, idazoxan, as was alpha-MeHA by pretreatment with the highly selective histamine H3 antagonist, thioperamide. Taken together, the results are consistent with blockade by prejunctional alpha 2, histamine H3 and probably somatostatin receptors which may be coupled to inhibition of neuropeptide release. Because 5-HT1-like agonists, which are useful for treating migraine and related headaches, share similar inhibitory properties in this in vivo model, the significance of prejunctional alpha 2, histamine H3 and somatostatin receptors to treatment of vascular headaches is suggested.
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PMID:UK-14,304, R(-)-alpha-methyl-histamine and SMS 201-995 block plasma protein leakage within dura mater by prejunctional mechanisms. 128 76

The vasoconstrictor effect of endothelin-1 is long-lasting and slow in onset, suggesting that this peptide may be involved with long-term vascular responses. Substance P, a quick-acting, vasodilatory tachykinin present in sensory nerves, may be released by trigeminal fibres and thereby participate in the regulation of vascular tone in the head. Given the potential role of vasoregulatory peptides in the ocular-forehead circulation in the pathophysiology of vascular headaches, the interactions between substance P and endothelin-1 over time were studied in isolated porcine ophthalmic artery. Substance P-induced relaxation of precontracted artery segments was significantly diminished by endothelin-1, despite the fact that endothelin-1 itself had no further significant contractile effect on these arteries. It is also noteworthy that the observed reduction of substance P-induced relaxation occurred much more rapidly than the onset of endothelin-1-induced contraction in relaxed porcine ophthalmic artery. The results suggest an inhibitory synergism between endothelin-1 and substance P in this vascular bed.
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PMID:Endothelin-1 inhibits the vasodilation induced by substance P in isolated porcine ophthalmic artery. 128 99

The peptidergic and serotoninergic innervation of the rat dura mater was investigated by reacting dural wholemounts immunohistochemically with antibodies to calcitonin gene-related peptide (CGRP), substance P (SP), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), and serotonin (5-HT). CGRP and SP innervations of the dura were robust and the patterns of distribution of these neuropeptides were essentially the same. The majority of the fibers were perivascular and distributed to branches of the anterior and middle meningeal arteries and to the superior sagittal and transverse sinuses. Other CGRP/SP fibers appeared to end "free" within the dural connective tissue. NPY-immunoreactive fibers were extremely numerous and also distributed heavily to the branches of the meningeal arteries, the venous sinuses, and to the dural connective tissue. The pattern of NPY innervation resembled in many ways that of CGRP/SP; however, NPY innervation of the sinuses was greater and NPY perivascular fibers supplying the meningeal arteries formed more intimate contacts with the walls of the vessels. The pattern of VIP innervation was, in general, similar to that observed for the three previous neuropeptides; however, the overall density was considerably less. Small to moderate numbers of serotoninergic nerve fibers were observed in some, but not all, of the duras processed for 5-HT. The latter fibers were almost exclusively perivascular in distribution. Dural mast cells were prominently stained in the 5-HT preparations because of their serotonin content. Mast cells were also labeled in a nonspecific fashion in some of the tissues reacted immunohistochemically for neuropeptides; some of them were located in close apposition to passing nerve fibers. This study represents, to our knowledge, the first comprehensive work on the peptidergic and serotoninergic innervation of the mammalian dura mater. The results should increase our understanding of the roles that these fibers play in normal dural physiology and of their potential interactions in the pathogenesis of vascular headache.
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PMID:Peptidergic and serotoninergic innervation of the rat dura mater. 171 22

1. We describe the actions of GR43175, a 5-hydroxytryptamine1 (5-HT1)-like receptor agonist, on neurogenically-mediated plasma protein extravasation within an important pain-sensitive intracranial tissue, the dura mater. 2. GR43175 markedly attenuated extravasation of 125I-albumin from blood vessels within ipsilateral dura mater when administered to rats (100 micrograms kg-1) fifteen minutes before unilateral electrical trigeminal stimulation (1.2 mA, 5 Hz, 5 ms, 5 min); the ratio (stimulated/unstimulated sides) decreased from 1.81 to 1.23, P less than 0.005). 3. GR43175 (100 micrograms kg-1, i.v., rats; 30 micrograms kg-1, guinea-pigs) decreased the leakage of radiolabelled albumin from 163% to 119% (P less than 0.005, guinea-pig) or from 174 to 118% (P less than 0.05, rat) above vehicle-treated controls when injected ten minutes before systemic capsaicin treatment (0.5 or 1 mumol kg-1, i.v.). 4. GR43175 (30-300 micrograms kg-1) did not block plasma protein extravasation within extracranial tissues of rats and guinea-pigs innervated by the trigeminal nerve (conjunctiva, eyelid and lip). 5. The protein leakage which followed the i.v. administration of 5-HT (1 mumol kg-1) or neuropeptides which mediate neurogenic plasma extravasation, substance P (0.3 nmol kg-1 or 1 nmol kg-1) and neurokinin A (1 nmol kg-1), was not blocked by GR43175 (100, 300 micrograms kg-1) despite the presence of leakage in amounts equivalent to that following neurogenic stimulation. 6. GR43175 (100 micrograms kg-1) decreased bradykinin (10 mumol kg-1)-induced extravasation from 142 to 115% above vehicle-treated animals (P less than 0.05). 7. These results demonstrate an important action of GR43175 on neurogenic mechanisms in dural blood vessels. Since the ergot alkaloids possess a similar profile of drug activity, it is suggested that drugs useful in the treatment of acute vascular headaches may share a similar mechanism of action.
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PMID:The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater. 215 35

A complex network of neurotransmission systems underlies the control of the cerebral circulation. Classical neurotransmitters, vasoactive peptides and receptors have been found in cerebral arteries. Central and peripheral structures are also probably involved in the neurogenic control of the cerebral circulation. Vascular and neurotransmission changes reported in vascular headaches suggest that an alteration of the neurogenic control of the brain circulation may be implicated in vascular headaches. In particular, locus coeruleus, which may control the intracerebral adrenergic pathway, can induce vascular changes similar to those of migraine. Moreover, the trigeminal ganglion, which may induce the release of substance P, can change the extracranial and intracranial vasodilator activity. The vascular theory of migraine, proposed by Wolff, is re-evaluated on the grounds of a possible mediation of the vascular responses by neurotransmitters. It is hypothesized that a deficient modulation by enkephalins may cause alterations of locus coeruleus and/or trigeminal ganglion. The problem of pain in vascular headaches is also considered: whether it is of vascular origin or whether it is due to a dysfunction of the central nociceptive pathway. Knowledge of the neurogenic control of the cerebral circulation may be useful in understanding some pathogenetic mechanisms of vascular headaches.
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PMID:Vascular headaches and cerebral circulation: an overview. 241 Jan 34

The goal of this study was to examine vascular responses of the dura mater. Microspheres were used to measure blood flow to the dura and brain in anesthetized dogs. Under control conditions, blood flow to the dura was 38 +/- 3 (SE) ml.min-1.100 g-1. Values for blood flow to the dura obtained with simultaneous injection of 15- and 50-microns microspheres were similar, which suggests that shunting of 15-microns spheres was minimal. Left atrial infusion of substance P (100 ng.kg-1.min-1) and serotonin (40 micrograms.kg-1.min-1), two agonists that have been reported to increase vascular permeability in the dura, increased blood flow to the dura two- to threefold. Adenosine (iv) produced vasodilatation in the dura. Adenosine and serotonin did not affect cerebral blood flow, but substance P increased blood flow to the brain by approximately 40%. Seizures, which produce pronounced dilatation of cerebral vessels despite activation of sympathetic nerves, produced vasoconstriction in the dura. Thus 1) the dura is perfused at a relatively high level of blood flow under normal conditions and is very responsive to vasoactive stimuli, and 2) substance P and serotonin, which have been implicated in the pathogenesis of vascular headache, produce pronounced vasodilator responses in the dura mater.
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PMID:Vascular responses of dura mater. 247 56

While the presence of a robust perivascular neural network accompanying cerebral and dural blood vessels that contain various neuropeptides is well documented, the functional significance of this innervation is unclear. Following experimentally induced subarachnoid haemorrhage (SAH) in animal models, immunocytochemical studies have revealed that changes occur in the staining intensity of some of these neuropeptides. This study compared the immunostaining intensity of calcitonin-gene-related peptide (CGRP) and substance P (SP) in cerebral and dural perivascular nerve fibers after SAH in the rat. Subarachnoid haemorrhage was produced by injecting 0.3 ml of autologous blood into the cisterna magna of male Sprague Dawley rats. Sham operated animals received an equal volume of buffered lactated Ringer's solution (pH 7.4). Changes in the immunostaining intensity of cerebral and dural vessels were evaluated by independent observers at 6, 24, and 48 hours after SAH. Immunostaining of CGRP was reduced in cerebral vessels at 6 hours and returned to normal by 48 hours. In contrast, CGRP immunostaining of dural perivascular nerve fibers was unchanged at all time periods examined. A marked decrease in SP immunostaining was documented at 6 hours in both the cerebral and dural vessels in all animals; at 48 hours, the staining intensity had returned to control levels. These results support the idea that several subpopulations of trigeminovascular neurons containing CGRP, SP, or both project to cerebral and dural vessels. Since these subpopulations may be differentially activated in pathologic conditions, such as SAH or vascular headache, the potential exists for pharmacologic intervention of specific neuropeptides with the resultant abatement of a pathologic process.
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PMID:Effect of subarachnoid haemorrhage on trigeminovascular calcitonin-gene-related peptide and substance P of the rat dura mater versus cerebral vasculature. 752 75

Experimental data point to a determinant role for endothelial cell (EC) anionic sites in the regulation of vascular permeability. Previous studies have shown that EC anionic sites density is reduced in conditions of enhanced permeability. The pathophysiology of migraine and vascular headache encompasses dilatation of dural vessels and extravasation of plasma proteins. The current study was carried out to determine if the density of EC anionic sites is reduced in enhanced permeability of dural vessels. Enhanced permeability was chemically induced in rats by intravenous injection of substance P and was tested by assessing leakage of horseradish peroxidase (HRP). Anionic sites were labelled with cationic colloidal gold and their density was quantified from electron microscopy negatives. Experimental animals showed increased leakage of HRP from dural vessels. However, anionic sites in EC membranes (luminal and abluminal) showed no statistical differences when their mean densities in experimental and control animals were compared. The results indicate that in this model, factors other than the density of anionic sites may be important determinants in the permeability of dural vessels. Such factors may include structural alteration of ECs consistent with an increased permeability. In this study pronounced ultrastructural changes in ECs were noted in experimental animals including widening of intercellular junctions and an increase in the number of EC gaps and vesicles.
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PMID:Substance P-induced enhanced permeability of dura mater microvessels is accompanied by pronounced ultrastructural changes, but is not dependent on the density of endothelial cell anionic sites. 1009 Jun 78

In intracranial structures unmyelinated C- and Adelta-fibers of the trigeminal nerve transmit pain stimuli from meninges to the trigeminal nucleus caudalis (Sp5C). Peripheral nerve endings surround meningeal vessels (the so-called trigeminovascular system) and contain vasoactive neuropeptides (calcitonin gene-related peptide, substance P and neurokinin A). Activation of the trigeminovascular system promotes a meningeal sterile inflammatory response through the release of neuropeptides by peripheral endings. Orthodromic conduction along trigeminovascular fibers transmits information centrally with induction of immediate early c-fos gene within post-synaptic Sp5C neurons, as a marker of neuronal activity within central nociceptive pathways. In laboratory animals the system is activated by either electrical stimulation of the TG, chemical stimulation of the meninges, electrical or mechanical stimulation of the superior sagittal sinus or by induction of cortical spreading depression. All these techniques induce c-fos within Sp5C and are used as a rodent/feline model of vascular headache in humans. Up-to-date there is evidence that at least ten receptors (5-HT(1B), 5-HT(1D), 5-HT(lF), 5-HT(2B), NK-1, GABA(A), NMDA, AMPA, class III metabotropic glutamate receptors, and opioids mu receptors) modulate c-fos expression within Sp5C. These receptors represent potential targets for anti-migraine drugs as shown by triptans (5-HT(1B/1D/1F)) and ergot alkaloids (5-HT(1A1B/1D/1F)). This review discusses the importance of c-fos expression within Sp5C as a marker of cephalic nociception, the different cephalic pain models that induce c-fos within Sp5C, the receptors involved and their potential role as targets for anti-migraine drugs.
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PMID:Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. 1124 84

A bi-directional relationship between depression and migraine has been widely reported in epidemiological and clinical studies, but the mechanisms of interaction between these disorders have not been fully examined using animal models. The aim of the present study was to investigate the effects of depression elicited by olfactory bulbectomy (OB) on trigeminovascular nociception in conscious rats. The nociception was induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus (SSS); this procedure causes nociception similar to that experienced during vascular headaches such as migraine. We showed that nociceptive behaviors (grooming and head flicks) were significantly enhanced in OB rats as compared to sham-operation (Sham) rats and that these nociceptive behaviors were correlated with depressive-like behaviors. Systemic administration of the antidepressant amitriptyline (AMI) significantly alleviated nociceptive behaviors in both the OB rats and Sham rats. Plasma levels of substance P (SP), but not plasma calcitonin gene-related protein (CGRP), significantly increased in OB rats and plasma SP levels decreased to normal following AMI treatment. Furthermore, changes in plasma SP levels were associated with both depressive-like behaviors and nociceptive behaviors. In conclusion, our results indicate that OB-induced depression can exacerbate trigeminovascular nociception, which may be mediated by SP. Moreover, we demonstrate that inhibition of SP release may contribute to the antinociceptive effect of AMI.
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PMID:The effects of OB-induced depression on nociceptive behaviors induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus. 2200 86


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