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 tachykinins are a family of peptides with putative neurotransmitter roles in the nervous system. They mediate their effects via neurokinin-1, neurokinin-2 and neurokinin-3 receptors. There has been increasing interest in the therapeutic application of the tachykinin neurokinin-1 receptor antagonists in the treatment of pain and emesis, and more recently in depression. However, the central role of neurokinin-1 receptors is not well understood. The aims of the present study were to determine the behavioural responses of guinea-pigs, and the distribution of Fos-like immunoreactivity in the guinea-pig brain, following intracerebroventricular administration of the neurokinin-1 receptor-selective agonist, [Sar9,Met(O2)11]substance P. The effects of pretreatment with the neurokinin-1 receptor antagonist, SR 140333, were also investigated. Administration of [Sar9,Met(O2)11]substance P induced increased locomotor activity, as well as face washing, grooming and wet-dog shake behaviours, all of which were inhibited by the neurokinin-1 receptor antagonist, SR 140333, indicating the involvement of neurokinin-1 receptors. In order to localize the brain regions activated by [Sar9,Met(O2)11]substance P, the distribution of neurons expressing Fos-like immunoreactivity was examined. [Sar9,Met(O2)11]substance P induced increased Fos-like immunoreactivity in widespread areas, including the frontal cortex, hippocampus, amygdala, thalamus, hypothalamus, periaqueductal gray, area postrema and nucleus of the solitary tract. SR 140333 reduced Fos-like immunoreactivity induced by [Sar9,Met(O2)11]substance P in most areas. Thus, brain regions associated with emotion, sensation, learning and memory, autonomic regulation and emesis were activated by stimulation of neurokinin-1 receptors. The present data have added a functional domain to previous neurokinin-1 receptor localization studies by describing the extensive regions of the CNS that may be activated by stimulation of these receptors, and the potential of neurokinin-1 receptor antagonists to inhibit activation of these regions.
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PMID:Distribution of Fos-like immunoreactivity in guinea-pig brain following administration of the neurokinin-1 receptor agonist, [SAR9,MET(O2)11]substance P. 1057 26

Substance P (SP) is a member of the tachykinin family of bioactive peptides and has highest affinity for the NK-1 receptor. We have developed the non-peptide compound HSP-117 as a selective antagonist of the NK-1 receptor. Binding of 3H-SP to the membranes of IM-9 cells was inhibited by the antagonists HSP-117 and CP-99,994, the inhibitory activity of HSP-117 being 50-fold that of CP-99,994. The SP-induced firing responses of single neuron activity in slices of the nucleus tractus solitarius of ferrets were inhibited by 10 microM HSP-117. Intracerebroventricular injection of HSP-117 significantly inhibited retching and vomiting induced by copper sulphate and morphine and the inhibitory effect of HSP-117 on emesis was greater than that of CP-99,994. Moreover, emesis induced by copper sulphate and morphine were inhibited by the microinjection of HSP-117 and CP-99,994 into the area postrema and by lesion of the area postrema. These results indicate that HSP-117 is a potent anti-emetic agent, blocking NK-1 receptors in the area postrema and that NK-1 receptors in the area postrema play an important role in emesis induced by broad-spectrum emetic stimuli.
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PMID:[The role of tachykinin NK-1 receptors in emetic action in the area postrema of ferrets]. 1062 82

Nearly 30% of patients treated with metformin experience gastrointestinal side effects. Since release of 5-hydroxytryptamine (5-HT) from the intestine is associated with nausea, vomiting, and diarrhea, we examined whether metformin induces 5-HT release from the intestinal mucosa. In 40% of tissue biopsy specimens of human duodenal mucosa, metformin (1, 10, and 30 microM) caused an increase in 5-HT outflow by 35, 70, and 98%, respectively. Peak increases in 5-HT outflow were observed after 10-15 min exposure to metformin, returning to baseline levels after 25 min. Tetrodotoxin (1 microM) reduced by about 50% the metformin-evoked increase in 5-HT outflow (P<0.05). Metformin-evoked release was not affected by scopolamine + hexamethonium, propranolol, the 5-HT3 receptor antagonist dolasetron, naloxone, or the NK1 receptor antagonist L703606. In the presence of tetrodotoxin (1 microM), somatostatin (1 microM) further reduced metformin-induced 5-HT release by 15-20%. In view of the 5-HT releasing effects of selective 5-HT3 receptor agonists to which metformin (N-N-dimethylbiguanide) is structurally related, we investigated whether metformin directly interacts with 5-HT3 receptors. Receptor binding (inhibition of [3H]-GR65630 binding) and agonist effects (stimulation of [14C]-guanidinium influx) at 5-HT3 receptors were studied in murine neuroblastoma N1E-115 cells, which express functional 5-HT3 receptors. Metformin up to 0.3 mM failed to inhibit [3H]-GR65630 binding and to modify displacement of [3H]-GR65630 binding induced by 5-HT. 5-HT (3 microM) stimulated the influx of [14C]-guanidinium in intact N1E-115 cells. Metformin up to 1 mM failed to modify basal influx, 5-HT-induced influx, and 5-HT+ substance P-induced influx of [14C]-guanidinium. Our results indicate that metformin induces 5-HT3 receptor-independent release of 5-HT from human duodenal mucosa via neuronal and non-neuronal mechanisms. Part of the gastrointestinal side effects observed during treatment with metformin could, thus, be produced by the release of 5-HT and other neurotransmitter substances within the duodenal mucosa.
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PMID:Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors. 1065 Nov 52

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

The development of small-molecule antagonists of the substance P (SP)-preferring tachykinin NK1 receptor during the past decade represents an important opportunity to exploit these molecules as novel therapeutic agents. On the basis of its anatomical localization and function, SP has been implicated in diverse pathophysiologies; of these, diseases of the CNS have been examined in the greatest detail. Although SP is best known as a pain neurotransmitter, it also controls vomiting and various behavioural, neurochemical and cardiovascular responses to stress. Recent clinical trials have confirmed the efficacy of NK1 receptor antagonists to alleviate depression and emesis but, surprisingly, not pain. Thus, multiple clinical trials, targeted to appropriate patient populations, are necessary to define the therapeutic potential of novel neurotransmitter ligands.
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PMID:Discovery of the antidepressant and anti-emetic efficacy of substance P receptor (NK1) antagonists. 1067 Nov 76

Delayed emesis in cancer patients undergoing chemotherapy remains a significant problem. The pathogenesis of delayed emesis is still obscure. It was recently demonstrated that methotrexate (MTX), an anticancer drug, evoked delayed emesis in dogs in a manner similar to its actions in humans. We evaluated the antiemetic activity of FK1052, a potent antagonist for both the 5-hydroxytryptamine (HT)(3) and 5-HT(4) receptors, on delayed emesis induced by MTX in beagle dogs. Animal behavior was recorded for 3 days using a video camera. Delayed emesis lasting up to 72 h was observed in dogs treated with MTX (2.5 mg/kg i.v.), but acute emesis did not occur. The following antiemetics, at the dose that prevents cisplatin-induced acute emesis in dogs, were administered i.v. as multiple injections every 12 h during days 2 to 3. FK1052 (1 and 3.2 mg/kg) significantly reduced the emetic episodes caused by MTX, whereas ondansetron (1 mg/kg), a selective 5-HT(3) receptor antagonist, was not effective. The emetic episodes induced by MTX were also inhibited by another 5-HT(3/4) receptor antagonist, tropisetron (1 mg/kg). CP-122,721 (0. 1 mg/kg), a potent selective tachykinin NK(1) receptor antagonist, significantly reduced the emetic responses to MTX. Copper sulfate-induced emesis in dogs was also prevented by FK1052, tropisetron, and CP-122,721 but not by ondansetron. FK1052, tropisetron, and ondansetron had negligible affinity for the NK(1) receptor at 1 microM. These results suggest that the 5-HT(4) receptor may be in part involved in the production of delayed emesis induced by MTX in dogs and that FK1052 may be a useful drug against both acute and delayed emesis induced by cancer chemotherapy.
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PMID:Probable involvement of the 5-hydroxytryptamine(4) receptor in methotrexate-induced delayed emesis in dogs. 1068 16

The anti-emetic profile of the novel brain penetrant tachykinin NK1 receptor antagonist MK-0869 (L-754,030) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluor o)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine and its water soluble prodrug, L-758,298, has been examined against emesis induced by cisplatin in ferrets. In a 4 h observation period, MK-0869 and L-758,298 (3 mg/kg i.v. or p.o.) inhibited the emetic response to cisplatin (10 mg/kg i.v.). The anti-emetic protection afforded by MK-0869 (0.1 mg/kg i.v.) was enhanced by combined treatment with either dexamethasone (20 mg/kg i.v.) or the 5-HT3 receptor antagonist ondansetron (0.1 mg/kg i.v.). In a model of acute and delayed emesis, ferrets were dosed with cisplatin (5 mg/kg i.p.) and the retching and vomiting response recorded for 72 h. Pretreatment with MK-0869 (4-16 mg/kg p.o.) dose-dependently inhibited the emetic response to cisplatin. Once daily treatment with MK-0869 (2 and 4 mg/kg p.o.) completely prevented retching and vomiting in all ferrets tested. Further when daily dosing began at 24 h after cisplatin injection, when the acute phase of emesis had already become established, MK-0869 (4 mg/kg p.o. at 24 and 48 h after cisplatin) prevented retching and vomiting in three out of four ferrets. These data show that MK-0869 and its prodrug, L-758,298, have good activity against cisplatin-induced emesis in ferrets and provided a basis for the clinical testing of these agents for the treatment of emesis associated with cancer chemotherapy.
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PMID:The novel NK1 receptor antagonist MK-0869 (L-754,030) and its water soluble phosphoryl prodrug, L-758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets. 1072 86

Many gastrointestinal stimuli result in gastric fundic relaxation. This information is integrated at the interface of vagal afferents and efferents in the dorsal vagal complex. Substance P (SP) is present in this region, and the neurokinin(1) receptor (NK(1)R) is highly expressed in preganglionic neurons of the dorsal motor nucleus of the vagus (DMN). However, its functional effects on vagal motor output to the stomach have not been investigated. Therefore, we determined the gastric motor effects of stereotaxic microinjection of SP and selective tachykinin receptor agents into the DMN of anesthetized rats. Dose-related decreases in intragastric pressure and antral motility were obtained on the microinjection of SP (135 and 405 pmol) into the DMN, without cardiovascular changes. Similar decreases in intragastric pressure were noted after the microinjection of [Sar(9),Met(O(2))(11)]SP (NK(1)R agonist; 135 pmol) but not senktide (NK(3)R agonist; 135 pmol) or vehicle. The gastric motor inhibition evoked by SP (135 pmol) was attenuated by prior microinjection of 2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-yl)-a mine (GR203040; 1 nmol; NK(1)R antagonist). Vagotomy or hexamethonium (15 mg/kg i.v.) completely abolished the gastric relaxation evoked by SP (135 pmol) microinjected into the DMN. We conclude that SP acts on NK(1)R preganglionic cholinergic vagal neurons in the DMN, which control enteric nonadrenergic noncholinergic motor inhibition of the fundus. The potential relevance is that an antiemetic site of action of NK(1)R antagonists may be in the DMN to prevent excitation of neurons controlling fundic relaxation, which is an essential prodromal component of emesis.
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PMID:Substance P in the dorsal motor nucleus of the vagus evokes gastric motor inhibition via neurokinin 1 receptor in rat. 1073 72

The role of tachykinin NK-1 receptors in the area postrema (AP) in emesis was examined in ferrets. Strong c-fos-like immunoreactivity was observed in the AP and nucleus tractus solitalius (NTS) in cisplatin (10 mg/kg, i.p.)-treated animals, but not in control animals. The number of the central emetogen morphine-induced vomits and retches was remarkably reduced (95%) and that of the peripheral emetogen copper sulphate-induced vomits was significantly (54%) reduced by AP lesion. Pretreatment with the tachykinin NK-1 receptor antagonists HSP-117 (1.0 microg) and CP-99,994 (7.5 microg) into the AP decreased the numbers of vomits and retches induced by morphine and copper sulphate. These results suggest that NK-1 receptors in the AP are involved in the mechanism of emesis induced by morphine and copper sulphate.
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PMID:The role of tachykinin NK-1 receptors in the area postrema of ferrets in emesis. 1082 52

Inflammatory infiltration of intestinal myenteric plexuses (i.e. myenteric ganglionitis), along with severe intestinal motor abnormalities, may accompany paraneoplastic syndromes, neurological disorders and gastrointestinal infections, although rare cases can be idiopathic. In this report, we describe the case of a patient who presented with chronic intractable vomiting and weight loss associated with idiopathic myenteric ganglionitis mainly involving the stomach. Tissue analysis showed that the inflammatory infiltrate comprised T lymphocytes (CD4+ and CD8+), and peptide immunolabelling revealed a marked decrease of substance P/tachykinin immunoreactive staining in nerve fibres and myenteric neurones. Following systemic steroid therapy, the patient's symptoms dramatically improved, and after one year of follow-up his general condition remains satisfactory. The possible mechanisms leading to symptom generation and gastric dysmotility in the context of an idiopathic myenteric ganglionitis are discussed.
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PMID:Idiopathic myenteric ganglionitis underlying intractable vomiting in a young adult. 1091 77


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