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)

Interaction between the 5-HT4 receptor and cholinergic-dependent and -independent contraction of the rat oesophageal muscularis mucosae was determined. Substance P- (in the presence of atropine) and carbachol-precontracted tissue was relaxed by tryptamines and the substituted benzamides with the following rank order of potency: 5-HT > 5-methoxytryptamine > cisapride > (R)-zacopride > lintopride > metoclopramide, consistent with 5-HT4 receptor activation. The response to 5-HT was not antagonized by tetrodotoxin, methysergide or ondansetron; but was shifted to the right by GR113808 ([1-[2-[methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-1-H- indole-3-carboxylate) in substance P- and carbachol-precontracted tissue, confirming 5-HT4-mediated relaxation. This study shows for the first time that although 5-HT4 receptors are involved in the modulation of cholinergic neurotransmission they can also act independently of this system modulating tachykinergic responsiveness.
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PMID:Post-synaptic 5-HT4 receptor modulation of tachykinergic excitation of rat oesophageal tunica muscularis mucosae. 912 43

The increased plasma protein extravasation in the airways of Fisher 344 rats upon stimulation of sensory nerves is in part due to the degranulation of mast cells. In this study, we examined the role of 5-HT and histamine receptors in the capsaicin-induced increase in plasma protein extravasation in Fisher 344 rat airways, using Evans blue as an intravascular marker. We found that only 5-HT2 receptor agonists increased baseline plasma protein extravasation. Furthermore, the 5-HT2 receptor antagonist ketanserin reduced the capsaicin-induced increase in plasma protein extravasation. Combining ketanserin with the tachykinin NK1 receptor antagonist (+/-)-RP 67,580 ((3alphaR,7alphaR)-(7,7-diphenyl-2(1-imino-2-(2-methoxyph enylethyl)-perhydraisoinositol-4-one))) abolished the neurogenic increase in plasma protein extravasation. Finally, using selective receptor agonists and antagonists, we demonstrated that there was no modulation of the capsaicin-induced rise in plasma protein extravasation by stimulation of either histamine receptors or 5-HT1, 5-HT3 and 5-HT4 receptors. We conclude that, in the airways of Fisher 344 rats, the neurogenic increase in plasma protein extravasation is caused by activation of both tachykinin NK1 receptors and 5-HT2 receptors.
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PMID:Role of the 5-HT receptor in neurogenic inflammation in Fisher 344 rat airways. 914 80

1. In the Fisher 344 rat, tachykinins have been shown to cause the release of 5-hydroxytryptamine (5-HT) from airway mast cells, which then causes direct smooth muscle activation as well as the release of acetylcholine from cholinergic nerves. The aim of the present study was to examine the modulatory effects of 5-HT receptors on the neurokinin A (NKA)-induced release of endogenous 5-HT and airway smooth muscle contraction in the isolated Fisher 344 rat trachea. 2. The selective 5-HT2 receptor antagonist ketanserin (0.1 microM) produced an almost complete inhibition of the contractions caused by NKA (n=4, P<0.0001, two-way ANOVA), and a significant rightward shift of the concentration-response curve to 5-HT (n=8, P<0.001, two-way ANOVA). 3. The partial agonist for 5-HT1A receptors, 8-OH-DPAT (1 microM), and the full agonist for 5-HT1 receptors, 5-CT (0.3 microM), potentiated the submaximal contractions induced by the 5-HT2 receptor agonist alpha-methyl-5-HT (0.1 microM) (n=4; P<0.005 and P<0.05, respectively). 8-OH-DPAT (1 microM), as well as the 5-HT1A receptor antagonists pMPPI, SDZ 216525 and NAN-190 (0.1 microM each), caused significant inhibition of the tracheal contractions induced both by NKA (10 nM-3 microM) and 5-HT (10 nM-10 microM) (n=4-10). This suggests that activation of 5-HT1A receptors potentiates the 5-HT2 receptor-mediated contractions. 4. SDZ 216525 (0.1 microM) significantly reduced the maximal contraction produced by 1 microM NKA (n=10, P< 0.001), without affecting the release of endogenous 5-HT. These data rule out the involvement of a 5-HT1A receptor-mediated positive feedback mechanism of the 5-HT release from mast cells. 5. Even in the presence of atropine (1 microM), 8-OH-DPAT (1 microM) further reduced the maximal NKA-induced contraction (n=4, P<0.0001), while the contractions of the rat isolated trachea induced by electrical field stimulation and the concentration-response curve to carbachol were unaffected by pMPPI (0.1 microM), SDZ 216525 (0.1 microM), NAN-190 (0.1 microM) and 8-OH-DPAT (1 microM) (n=4-6). These data demonstrate that the 5-HT1A receptor-mediated potentiation of contractile responses is not due to nonspecific inhibition of airway smooth muscle contraction or to modulation of postganglionic nerve activation. 6. The selective 5-HT1B/1D receptor antagonist GR 127935, the selective 5-HT3 receptor antagonist tropisetron and the selective 5-HT4 receptor antagonists SB 204070 and GR 113808 (0.1 microM each) had no effect on the concentration-response curve for NKA (n=6-10), ruling out the involvement of 5-HT1B/1D, 5-HT3 and 5-HT4 receptors. 7. The alpha-adrenoreceptor antagonist phentolamine (1 microM) had no effect on the 5-HT-induced contractions (n=4), ruling out the involvement of alpha-adrenoreceptors. 8. In conclusion, the tachykinin-induced contraction of the F334 rat isolated trachea is mediated by the stimulation of 5-HT2 receptors. Activation of 5-HT1A receptors located on airway smooth muscle potentiates the direct contractile effects of 5-HT2 receptor activation. The 5-HT1B/1D, 5-HT3 and 5-HT4 receptors are not involved in the NKA-induced contraction of rat airways.
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PMID:Modulation by 5-HT1A receptors of the 5-HT2 receptor-mediated tachykinin-induced contraction of the rat trachea in vitro. 960 63

Quantitative autoradiography was used to examine possible adaptive changes in serotonin 5-HT1B/1D and 5-HT2A/2C receptor binding sites in adult rat basal ganglia, after partial or severe lesions of serotonergic neurons produced by intraraphe injections of variable amounts of 5,7-dihydroxytryptamine. In controls, the 5-HT1B/1D sites labeled with S-CM-G[125I]TNH2 were evenly distributed in the core and the shell of the nucleus accumbens. The density of 5-HT1B/1D sites was higher in the ventral than dorsal part of the striatum and no regional differences were detected along the rostrocaudal axis of the structure. The 5-HT2A/2C sites labeled with [125I]DOI were preferentially distributed in the mediodorsal striatum and higher densities were detected in the shell than core of the nucleus accumbens. Following 5,7-dihydroxytryptamine injections, there were no changes in binding of either receptor subtype after partial lesions entailing 80-90% 5-HT depletions. After severe 5-HT depletions (over 95%), large increases in 5-HT1B/1D binding were observed in the substantia nigra (78%), but no changes took place in the globus pallidus. Increases in 5-HT1B/1D binding were also detected in the shell of the nucleus accumbens (27%). Similar sized increases in 5-HT2A/2C binding (22%) were restricted to the medial striatum. The present results suggest a preferential association between 5-HT1B/1D receptors and the striatonigral neurons containing substance P, as indicated by the striatal distribution of these receptors and their selective increases in the substantia nigra after severe 5-HT deprivation. We recently proposed a similar relationship between the 5-HT4 receptors and the striatopallidal neurons containing met-enkephalin. Moreover, the increases in 5-HT1B/1D binding in the substantia nigra and in the shell of the nucleus accumbens reinforce the view of an implication of this receptor subtype in motor functions. In contrast, the prominent increases in 5-HT2A/2C binding after severe 5-HT deprivation as restricted to the medial region of the striatum and suggest up-regulation of most probably 5-HT2C receptors in a region implicated in cognitive functions.
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PMID:Selective increases in serotonin 5-HT1B/1D and 5-HT2A/2C binding sites in adult rat basal ganglia following lesions of serotonergic neurons. 963 May 49

Significant progress has been made in recent years in developing more effective means of preventing nausea and vomiting induced by cancer chemotherapy. With appropriate application of currently available antiemetic regimens, the majority of patients with cancer who are receiving chemotherapy can anticipate experiencing no emesis during their treatment. Nevertheless, incompletely controlled emesis remains a problem for a significant percentage of patients. Persistent challenges include delayed emesis and emesis following high-dose chemotherapy regimens. The goal of complete prevention of emesis in all patients remains elusive. Therefore, there is a strong rationale for investigating new antiemetic approaches. New antiemetic agents currently under development target the neurotransmitters serotonin (5-hydroxytryptamine; 5-HT) and substance P. A number of new selective antagonists of serotonin 5-HT3 receptors are in clinical trials. Given the lack of clinically significant differences between the available 5-HT3 receptor antagonists, it appears unlikely that any of these new agents will have substantial advantages over currently approved agents. Several other serotonin receptors have been targeted including the 5-HT4, 5-HT1A and 5-HT2A receptors. Of these approaches, only agonism of the 5-HT1A receptor has produced an agent that has proceeded into clinical testing. The most exciting new class of antiemetics currently under development focuses on antagonism of the effects of the neurotransmitter substance P. Results of early clinical trials with tachykinin neurokinin NK1 receptor antagonists demonstrate enhanced control of acute emesis with their addition to currently available agents and promising activity in controlling delayed emesis. Available evidence would strongly suggest that this class of agents will represent the next important advance in efforts to control nausea and vomiting induced by chemotherapy.
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PMID:Antiemetics for cancer chemotherapy-induced nausea and vomiting. A review of agents in development. 1065 96

In this study the functional interaction of the antidepressant drugs amitriptyline, mianserin, maprotiline, imipramine, fluoxetine and the putative antidepressant drug flibanserin has been studied on 5-HT7-mediated responses to 5-carboxamidotryptamine (5-CT) in the guinea-pig ileum. 5-CT induced a concentration-dependent inhibition of the contractile response to substance P (100 nM). Except for fluoxetine and flibanserin, all the antidepressants antagonized by different degrees the 5-CT inhibitory response with the following rank affinity order: mianserin > maprotiline > imipramine > amitriptyline. Mianserin was the only antidepressant to show a profile of competitive antagonism at 5-HT7 receptors in a tenfold range of concentrations (0.1-1 microM), with an affinity (pA2) value of 8.1 +/- 0.6. The antagonism of the other antidepressants was not concentration-dependent (amitriptyline) or was associated with slight or moderate reduction of the maximal 5-CT response (imipramine or maprotiline). The apparent affinity (pKB) values were: amitriptyline, 7.0 +/- 0.2; maprotiline, 7.3 +/- 0.6; imipramine, 7.2 +/- 0.4. Our results show that various antidepressant drugs belonging to different chemical classes behave as antagonists at enteric 5-HT7 receptors through competitive or allosteric mechanisms. This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5-HT receptors, namely 5-HT3 and 5-HT4 receptors.
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PMID:The interaction of antidepressant drugs with enteric 5-HT7 receptors. 1099 31

The motor, modulatory, and sensory neurotransmitters that mediate the peristaltic reflex in the mouse colon were identified by direct measurement, and their involvement in various pathways was determined by selective receptor antagonists. Mucosal stimulation in the central compartment of a three-compartment flat sheet preparation of mouse colon elicited ascending contraction and descending relaxation in the orad and caudad compartments, respectively. Ascending contraction was accompanied by substance P release, a marker for excitatory neurotransmitter release, into the orad compartment and was partly inhibited by atropine and spantide, and abolished by a combination of the two antagonists. Descending relaxation was accompanied by vasoactive intestinal peptide (VIP) release, a marker for inhibitory neurotransmitter release, into the caudad compartment, and was partly inhibited by VIP10-28 and NG-nitro-L-arginine, and abolished by a combination of the two agents. Somatostatin release increased during descending relaxation: immunoneutralization of somatostatin or blockade of its effect with a selective somatostatin type 2 receptor antagonist inhibited descending relaxation. The delta-opioid receptor antagonist naltrindole augmented descending relaxation and ascending contraction. Calcitonin gene-related peptide (CGRP) release increased in the central compartment and was mediated by concurrent release of 5-hydroxytryptamine (5-HT) because its release was blocked by a 5-HT4 receptor antagonist. Both the latter and the CGRP antagonist CGRP8-37, inhibited ascending contraction and descending relaxation. Thus, the reflex in mouse like that in rat and human intestine is initiated by mucosal release of 5-HT and activation of 5-HT4 receptors on CGRP sensory neurons and is relayed via somatostatin and opioid interneurons to VIP/nitric-oxide synthase inhibitory motor neurons and via cholinergic interneurons to acetylcholine/tachykinin excitatory motor neurons.
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PMID:Neurotransmitters mediating the intestinal peristaltic reflex in the mouse. 1296 54

The symptomatic management of irritable bowel syndrome (IBS) and functional dyspepsia, which often overlap, can be frustrating and difficult. Education and reassurance remain central for management although controlled trials are lacking. Psychological interventions may be useful in select patients but methodological inadequacies in clinical trials limit their interpretability. For symptom exacerbations, drug treatment is reasonable but no current treatment successfully targets the full symptom complex. Bulking agents are not of proven efficacy in IBS; they may improve constipation but worsen bloating and pain. Anticholinergics are of uncertain value in IBS. A meta-analysis of trials of smooth muscle relaxants for IBS has been reported to be positive but the quality of the trials included was poor. Antidepressants for IBS and functional dyspepsia appear to be efficacious based on the limited published evidence; both global symptoms and abdominal pain improve. Selective serotonin reuptake inhibitors (SSRIs) are of uncertain efficacy but anecdotally appear to be useful. Laxatives are not of proven efficacy in IBS. Loperamide improves diarrhea, but not abdominal pain in IBS. No drug is of proven efficacy for bloating. Acid suppression remains the mainstay of therapy for functional dyspepsia but the majority of patients do not have an adequate response. Promising drugs include new prokinetics for constipation-predominant IBS (e.g., tegaserod, a partial 5-HT4 agonist, prucalopride, a full 5-HT4 agonist, and dexloxiglumide, a cholecystokinin1 antagonist), agents for diarrhea-predominant IBS (e.g., 5-HT3 antagonists, alpha2 receptor agonists and corticotrophin receptor-1 antagonists), other visceral analgesics (e.g. tachykinin antagonists, opioid agonists) and in dyspepsia fundus relaxing agents (e.g., 5-HT1 agonists, tegaserod).
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PMID:New and emerging treatments for irritable bowel syndrome and functional dyspepsia. 1598 38


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