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 intrathecal injection of substance P (SP) (2.5-15 micrograms) has been shown to produce hyperalgesia in the rat tail flick test. Repeated injection of SP (7.5 or 15 micrograms) or pretreatment with two of these doses produces desensitization to this hyperalgesic response. Desensitization is dose-related with respect to degree and duration. This phenomenon is relatively specific because the hyperalgesic response to methysergide, a serotonin receptor antagonist, is unaffected, while that produced by phentolamine, an adrenergic receptor antagonist, is much less affected than that of SP. Pretreatment with a desensitizing regimen of SP potentiates the antinociceptive effect of morphine and baclofen when they are tested immediately after the regimen but if a 30 min delay is permitted, an inhibition of their effects is observed. These results support the notion that the spinal antinociceptive effect of morphine and baclofen is due to an interaction with SP mechanisms in the spinal cord, the nature of which may be more complex than is presently understood. Desensitization produces no change in baseline responsiveness in the tail flick test. This suggests that the hyperalgesic response to SP is due either to an action at a site other than the primary afferent synapse, or if it is at this site either compensatory mechanisms occur or SP is not the primary determinant of tail flick latency but may play a modulatory role.
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PMID:Desensitization to substance P following intrathecal injection. A technique for investigating the role of substance P in nociception. 241 68

Both substance P and, to a lesser degree, serotonin activate cation permeability in neuroblastoma x glioma hybrid cells, as determined by measurement of [14C]guanidinium uptake. Serotonin potentiates the action of substance P by shifting the concentration-effect curve of substance P to the left. The EC50 value for the synergistic effect of serotonin was around 0.3 microM. Dopamine and noradrenaline displayed comparable activity, albeit only at 50 and 130 times higher concentrations, respectively. The order of potency of various substance P-analogues was not changed by serotonin, indicating that the specificity of the substance P site on the hybrid cells was not affected by serotonin. Various other neurotransmitters and peptides had no effect on the response of the hybrid cells to substance P. The serotonin receptor interacting with the substance P receptor may be classified as a 5-HT3-receptor since methysergide, cimetidine, and ketanserin were ineffective, but two inhibitors specific for 5-HT3-receptors, ICS 205-930 (3 alpha-tropanyl-1H-indole-3-carboxylic acid ester) and MDL 72222 (1 alpha H,3 alpha,5 alpha H-tropan-3-yl-3,5-dichlorobenzoate), blocked the effect of serotonin at nanomolar concentrations. However, the two serotonin antagonists might also be blocking the ion permeability, since at higher concentrations they fully inhibited the stimulation of guanidinium uptake by substance P or by substance P plus serotonin. The synergism between substance P and serotonin on the hybrid cells offers the opportunity to study the mechanism of interaction of neurotransmitter receptors on a permanent neuronal cell line.
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PMID:Substance P and serotonin act synergistically to activate a cation permeability in a neuronal cell line. 246 36

1. Four putative neurotransmitters (serotonin, substance P, ATP (alpha-beta-methylene-ATP), and vasoactive intestinal peptide, VIP) of the non-adrenergic non-cholinergic (NANC) innervation were examined for their role in the NANC excitatory neurotransmission in channel catfish intestine after adrenergic and cholinergic blockade. 2. VIP at concentrations ranging from 10(-12)M to 10(-4)M did not produce either a relaxant or a contractile response in these segments. 3. Serotonin, substance P and alpha-beta-methyl-ATP produced contractile responses in a dose-dependent manner. Their EC50 values were 5 x 10(-7)M, 5 x 10(-9)M and 5 x 10(-9)M and 5 x 10(-6)M, respectively. 4. Electrical field stimulation of the intestinal segments produced a predominant excitatory response after complete blockade of adrenergic and cholinergic divisions, suggesting a predominant NANC excitatory innervation. 5. Three types of serotonin receptor antagonists, namely methiothepin (predominantly a 5-HT1 antagonist), ketanserin (a selective 5-HT2 antagonist), methysergide and cyproheptadine (predominantly 5-HT2 blockers) and metoclopramide (a selective 5-HT3 blocker) were tested for their effectiveness against serotonin and EFS-induced contractions. Methiothepin, methysergide, cyproheptadine and metoclopramide produced significant blockade of the response to serotonin, whereas only methiothepin and cyproheptadine produced blockade of EFS-induced response. 6. Three agents tested for substance P blockade, namely spantide, 4-11 fragment of substance P, and methysergide (also a serotonin blocker), did not produce significant inhibition of the response to either substance P or EFS. 7. Suramin at a dose that blocked the ED50 concentration of ATP did not produce a significant blockade of the response to EFS suggesting that ATP-involvement in the NANC-e neurotransmission is unlikely. 8. This study confirmed the involvement of serotonin in the expression of non-adrenergic non-cholinergic excitatory response of the channel catfish intestine.
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PMID:Evidence for serotonin involvement in the NANC excitatory neurotransmission in the catfish intestine. 753 35

Whereas serotonin and substance P stimulate in-vivo and in-vitro myoelectric activity in the small intestine, their effects on transit are unclear. We used a validated in-vivo transit model in the chloral hydrate-anaesthetized rat to study the effects of serotonin, substance P and motilin, three putative mediators of carcinoid diarrhoea, on transit through the upper digestive tract. Intra-arterial serotonin accelerated gastric emptying of a radiolabelled liquid, while motilin accelerated overall upper gastrointestinal transit. Substance P slowed overall upper gastrointestinal transit without altering gastric emptying. The antagonists to serotonin receptor subtypes, R-zacopride (5-HT3) and ketanserin (5-HT2), also accelerated rat gastric emptying of liquids; in contrast, a 5-HT4 agonist, SC53116, resulted in a less pronounced effect on gastric emptying at the dose tested. We conclude that circulating substance P is unlikely to be an important accelerator of transit through the upper digestive tract; in contrast, hyperserotoninaemia significantly accelerates transit through the stomach, and 5-HT2 and 5-HT3 receptor subtypes may play a role in the motor effects of serotonin in the stomach.
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PMID:Effect of putative carcinoid mediators on gastric and small bowel transit in rats and the role of 5-HT receptors. 767 34

Vascular responses to endogenous agonists may determine patency rates of bypass graft conduits. The effect of constrictors (noradrenaline, phenylephrine, serotonin, histamine, angiotensin II) and dilators (acetylcholine, substance P, bradykinin, nitroglycerin) were compared in human internal mammary and inferior epigastric arteries in vitro. The latter vessel type has been recently advocated as an additional conduit for coronary artery bypass grafting. Whereas the alpha-adrenoceptor- (noradrenaline, phenylephrine) and serotonin receptor-mediated contractions were similar in both vessels, histamine-induced contractions were greatly enhanced in internal mammary arteries (maximal responses in percent of 80 mmol/L KCl, 131% +/- 15% versus 59% +/- 8%). Maximal contractions in response to angiotensin II were greater in inferior epigastric arteries (50% +/- 6% versus 25% +/- 5%). The endothelium-independent relaxations in response to nitroglycerin were identical in both vessels. In contrast, the endothelium-dependent relaxations in response to acetylcholine, substance P, and bradykinin were significantly greater in the inferior epigastric than in the internal mammary arteries (maximal relaxations expressed as percent of prostaglandin F2 alpha-induced precontraction: acetylcholine, 94% +/- 5% versus 77% +/- 5%; substance P, 85% +/- 4% versus 24% +/- 5%; bradykinin, 77% +/- 5% versus 26% +/- 3%). It is concluded that the inferior epigastric artery has a high endothelial capacity to release endothelium-derived relaxing factor. It appears that the inferior epigastric artery possesses credentials to be successfully used for coronary artery bypass grafting.
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PMID:Different vascular reactivity of human internal mammary and inferior epigastric arteries in vitro. 823 5

Human endothelin (ET) A receptor (hETAR) is a G-protein-mediated receptor that binds ET1 with high affinity and ET2 and ET3 with lower affinities. ET1 is the most potent endogenous vasoconstrictor known at this time. When expressed in Xenopus laevis oocytes, hETAR is rapidly desensitized after stimulation with ET1. This desensitization lasts 90-110 min. Human neurokinin A (hNKAR) and human serotonin type 2 receptors were also expressed in the Xenopus system for comparison to hETAR. hNKAR desensitizes for 25-35 min, while the serotonin receptor does not appear to desensitize. To examine the role of the cytoplasmic tail of hETAR in desensitization, deletion mutations were constructed which remove 11, 36, and 51 amino acids from the cytoplasmic tail. The mutations removing 11 and 36 residues were functional, but the mutation removing 51 amino acids was not functional. The two functional mutations have a resensitization time similar to that of hETAR. In summary, the prolonged desensitization time of hETAR is unique for G-protein-mediated receptors and may attenuate the adverse physiological effects of the endothelin family. In addition, the cytoplasmic tail of hETAR does not appear to play a role in desensitization or resensitization of this receptor.
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PMID:Prolonged desensitization of the human endothelin A receptor in Xenopus oocytes. Comparative studies with the human neurokinin A receptor. 825 20

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

Modulating monoamine activity as a therapeutic strategy continues to dominate antidepressant research, with a recent emphasis on agents with multiple targets, including combined serotonin/noradrenaline re-uptake inhibitors and numerous serotonin receptor ligands. An important new development has been the emergence of potential novel mechanisms of action, notably modulation of the activity of neuropeptides substance P and corticotrophin-releasing factor, and the intracellular messenger cyclic adenosine monophosphate. Efforts in this area have recently been rewarded by the demonstration of antidepressant efficacy of the substance P receptor antagonist MK-0869.
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PMID:Novel strategies for pharmacotherapy of depression. 1041 49

Serotonin, acetylcholine and substance P are mediators involved in the secretory response to cholera toxin in the small intestine. The aim of this study was to investigate the regional difference in the effect of a serotonin receptor type 3 antagonist (ondansetron), a nicotinic receptor antagonist (hexamethonium), and a substance P antagonist (the neurokinin receptor type 1 antagonist, CP 99,994) on the cholera toxin-induced fluid accumulation in the porcine jejunum. A dose-range of cholera toxin (0.32-56.00 microg/loop) was instilled for 4 hr in ligated loops in two regions of the proximal jejunum in 6-8-week-old pigs. Ondansetron (200 microg/kg), hexamethonium (10 mg/kg), CP 99,994 (1 mg/kg), or saline alone (control) were given intravenously 10 min. before cholera toxin instillation. Cardiovascular parameters, blood gas data, net fluid accumulation, serotonin and electrolyte concentration in the accumulated fluid were measured. Cardiovascular and blood gas parameters were within the normal range in all treatments. The apparent maximal response in fluid accumulation was reduced 20% in case of ondansetron, and by 33% using CP 99,994 in the aboral region compared to control, whereas no effect was observed in the oral region. Hexamethonium reduced the apparent maximal secretory response in both the oral and aboral regions by 45%. None of the treatments with antagonists changed the luminal content of serotonin or the electrolyte concentrations in the accumulated fluid. The results demonstrate that the involvement of serotonin receptor type 3 and neurokinin type 1 receptors in the transductional pathway of cholera toxin-induced fluid accumulation vary significantly within the jejunum, while the cholinergic (nicotinic) transmission plays an even role.
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PMID:Regional differences in neurogenic signal transduction pathway of cholera toxin-induced fluid, electrolyte and serotonin accumulation in the porcine jejunum. 1089 90

Plant extracts have been used for centuries as a popular mode of treatment for several health disorders. Over the last ten years, the study of those extracts has attracted attention in different fields of the biological sciences. Ginger, the rhizome of Zingiber officinale Roscoe (Zingiberaceae), is a commom constituent of diet worldwide and it has been reported that its extracts present some pharmacological activities. Here we investigate the effects of the crude hydralcoholic extract of ginger rhizomes on the classical models of rat paw and skin edema. The carrageenan-, compound 48/80- or serotonin-induced rat paw edema were inhibited significantly by the intraperitoneal administration of alcoholic ginger extract. Ginger extract was also effective in inhibiting 48/80-induced rat skin edema at doses of 0.6 and 1.8 mg/site. Rat skin edema induced by substance P or bradikinin was not affected by treatment with Z. officinalle extract. The intraperitoneal administration of ginger extract (186 mg/kg(-1) body wt.) 1 h prior to serotonin injections, reduced significantly the serotonin-induced rat skin edema. Our results demonstrated that crude extract of Zingiber officinale was able to reduce rat paw and skin edema induced by carrageenan, 48/80 compound and serotonin. The antiedematogenic activity seems to be related, at least partially, to an antagonism of the serotonin receptor.
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PMID:Anti-inflammatory effect of the hydralcoholic extract of Zingiber officinale rhizomes on rat paw and skin edema. 1283 2


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