Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The majority of substance P-like immunoreactive (SPLI) fibers in the lateral septal area (LS) are supplied by SPLI cells in the area (BAL) between the anterior hypothalamic nucleus and the lateral hypothalamus, and by those in the nucleus latero-dorsalis tegmenti (TLD). These conclusions are based on following: (1) Unilateral destruction of the BAL resulted in an ipsilateral decrease in the septal SPLI fibers similar to that seen after the destruction of the TLD, and (2) simultaneous destruction of the BAL and TLD caused a marked reduction of SPLI fibers in the LS on the operated side. The possibility that the destruction of the BAL affected the ascending SPLI system from the TLD seems to be excluded, because (1) the destruction of the TLD resulted in a decrease in SPLI fibers in the ipsilateral medial forebrain bundle (MFB), but failed to reduce the number of SPLI fibers in the BAL, and (2) the destruction of the BAL caused a decrease in SPLI fibers in the perifornical area rostral to the lesion, but failed to reduce the number of SPLI fibers in the MFB. These facts further suggest that ascending SPLI fibers from the BAL travel in the perifornical area and those from the TLD pass through the MFB. It should be noted that a few SPLI fibers remained intact following the simultaneous destruction of the BAL and TLD. The present study suggests that these remaining SPLI fibers might be innervated by intrinsic SPLI cells. In support of this, several SPLI cells were detected in the septal area after colchicine pretreatment.
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PMID:Origins of substance P-containing fibers in the lateral septal area of young rats: immunohistochemical analysis of experimental manipulations. 618 46

To investigate the role of IL-5 in airway hyperreactivity and pulmonary eosinophilia, we used a model of allergic asthma in guinea pigs and a neutralizing monoclonal antibody (TRFK-5) directed against murine IL-5. Sensitized guinea pigs were challenged with 1% ovalbumin (OVA) aerosol and assessed for airway eosinophilia (by bronchoalveolar lavage [BAL] and histologic evaluation of airway tissue) and bronchoconstrictor responsiveness to substance P (SP) (as RL100 and Cdyn40) 24 h later. OVA challenge of sensitized animals caused a significant increase in airway responsiveness to SP, with a 4.9-fold decrease in RL100 and a 4.7-fold decrease in Cdyn40. Accompanying this increased sensitivity to SP was a 9-fold increase in eosinophils recovered in BAL and a 4- to 5-fold increase in eosinophils in intrapulmonary bronchial tissue. Intraperitoneal treatment with 10 mg/kg of the IL-5 antibody 2 h before OVA challenge blocked BAL and lung tissue increases in eosinophils but had no effect on the development of airway sensitivity to SP. In contrast, similar treatment with 30 mg/kg of this antibody blocked OVA-induced increased sensitivity to SP as well as BAL and lung tissue eosinophilia. These data suggest a critical and possibly independent role for IL-5 in allergic airway hyperresponsiveness and the accumulation of eosinophils within the lung of the guinea pig.
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PMID:Inhibitory effect of the TRFK-5 anti-IL-5 antibody in a guinea pig model of asthma. 750 92

Three receptors for the tachykinins, NK1, NK2, and NK3, have been defined pharmacologically and have been cloned. We previously demonstrated that in Fisher 344 (F344) rats neurokinin A (NKA) and substance P (SP) cause bronchoconstriction mainly by indirect mechanisms that involve both cholinergic nerves and mast cells. Preliminary results suggested that in a less responsive strain, the BDE strain, tachykinins did not activate airway mast cells. We have now compared in F344 and BDE rats the airway effects of the tachykinins SP and NKA with those of specific NK1 and NK2 receptor agonists and have studied the effect of potent and specific nonpeptide NK1 and NK2 receptor antagonists on NKA-induced airway effects. Lung resistance (RL) and serotonin in bronchoalveolar lavage fluid (BAL 5HT) were measured in anaesthetized, mechanically ventilated, rats. In contrast to F344 rats, BDE rats were less sensitive to SP and NKA challenge, and no subsequent increase in BAL 5HT was observed. In F344 rats, the specific NK1 receptor agonists, [Sar9, Met(O2)11]SP and Ac[Arg6,Sar9,Met(O2)11]SP(6-11), caused a dose-dependent bronchoconstriction and increase in BAL 5HT comparable to those of NKA and SP. The NK1 receptor agonists had no effect in BDE rats. The NK2 receptor agonist [beta Ala8]NKA(4-10) caused a small, dose-dependent increase in RL in the F344 as well as in the BDE rat, but it had no effect on BAL 5HT. The NK1 receptor antagonists RP 67580 and CP 96,345 significantly reduced the increase in RL and BAL 5HT caused by NKA in the F344 rat, but they had no effect on the NKA-induced bronchoconstriction in the BDE rat.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vivo characterization of the tachykinin receptors involved in the direct and indirect bronchoconstrictor effect of tachykinins in two inbred rat strains. 751 94

The role of airway inflammation, induced by weekly antigen challenge, in the airway hyperresponsiveness to vagal (whole and NANC components) nerve stimulation and to neurotransmitters (acetylcholine and selective agonists for tachykinin NK1 and NK2 receptors) has been studied in the guinea-pig. Primarily, the time course (3, 7 and 14 days following the last challenge) of the effects of repeated aerosol antigen challenge on airway inflammation and bronchoalveolar fluid cellular composition was investigated. At 7 days following the last antigen challenge a maximal (as compared to 3 and 14 days) inflammatory response, in terms of a diffuse mild to marked infiltration of eosinophils, neutrophils and lymphocytes, was evident throughout pulmonary tissues. Only at this time some evidence of eosinophilia and neutropenia was detectable in BAL fluids. In these animals there was a normal bronchial responsiveness to iv administration of acetylcholine, selective synthetic agonists for the tachykinin NK2 receptors and capsaicin. On the other hand a remarkable airways hyperresponsiveness to iv administration of selective agonists for tachykinin NK1 receptors, as well as electrical stimulation of the vagal nerves (in presence and in absence of atropine), was detected. As a whole, these data indicate that at the peak of the inflammatory airway response following multiple antigen challenge there is a selective hyperresponsiveness to stimulation of vagal (mainly the non-adrenergic, non-cholinergic component) nerves associated with an increase in tachykinins (NK-1)-mediated bronchospasm.
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PMID:Hyperresponsiveness to non-adrenergic, non-cholinergic vagal stimulation following multiple antigen challenge in guinea-pigs. 853 95

In the guinea pig, interleukin-5 (IL-5) has been shown to induce airway hyperresponsiveness as well as eosinophilia, which are important symptoms in asthma. IL-5 seems to be a critical cytokine since it selectively affects eosinophil functions. The mechanism of action by which IL-5 leads to airway hyperresponsiveness may be important for our understanding of the pathogenesis of asthma. Neurogenic inflammation, which is mediated by nonadrenergic noncholinergic nerves (NANC), may play a role in the IL-5-induced effects in guinea pig airways. In this study, the role of neuropeptides in the IL-5-induced airway hyperresponsiveness and eosinophilia in the guinea pig was examined using selective neurokinin receptor antagonists. Intra-airway application of IL-5 (1 microgram, twice) induces a selective eosinophil migration (control: 12 [8-22] x 10(5) cells and IL-5: 90 [67-187] x 10(5) cells, p < 0.05) and activation (control: 6.3 +/- 0.9 ng eosinophil peroxidase [EPO]/ml bronchoalveolar lavage [BAL] fluid and IL-5: 29.3 +/- 4.9 ng EPO/ml BAL fluid, p < 0.05) and a pronounced airway hyperresponsiveness in vivo. The maximal responses to histamine are increased by 160 +/- 16% (p < 0.05) after IL-5. Treatment of guinea pigs with either the nonselective neurokinin (NK)-receptor antagonist, FK224, or the selective NK2-receptor antagonist, SR48968, results in a complete inhibition of the in vivo hyperresponsiveness found after application of IL-5. Vice versa, intra-airway administration of substance P (10 micrograms, twice) results in an airway hyperresponsiveness (increased maximal response after substance P: 166 +/- 15% [p < 0.05]) without inducing migration or activation of eosinophils. All examined NK-receptor antagonists do not influence the IL-5-induced eosinophil accumulation. In addition, no effect of the NK-receptor antagonists is observed on the IL-5-induced eosinophil activation, as determined by BAL fluid EPO levels. The release of NK2-receptor active tachykinins plays an important role in the development of IL-5-induced airway hyperresponsiveness. This feature appears to be a step following eosinophil infiltration and activation since there are no effects on eosinophil function by pretreatment of the used NK-receptor antagonists.
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PMID:Role for neurokinin-2 receptor in interleukin-5-induced airway hyperresponsiveness but not eosinophilia in guinea pigs. 927 11

Neuropeptides released from sensory nerves during inflammation have potent effects on bronchomotor tone, airway secretion, and inflammatory cells. We investigated the effects of ozone on sensory nerves by exposing 12 healthy, nonsmoking subjects to 0.2 ppm ozone and filtered air (FA) for 2 h on separate occasions, with intermittent exercise and rest. Spirometry was performed at baseline and 15 min after exposures, and bronchoscopy (bronchial biopsy and bronchoalveolar lavage [BAL]) was done 6 h after exposure. Frozen sections were immunostained for the anatomic neural marker protein gene peptide (PGP) 9.5 and the sensory neutropeptides substance P (SP) and calcitonin-gene-related peptide (CGRP). Nerves in the submucosa were quantified by image analysis. A trend toward an increase in the levels of polymorphonuclear leukocytes (PMNs) (air versus ozone, median [interquartile range]: 3.5 [2 to 5.3%] versus 9.8 [4.2 to 16.3%], p = 0.07) and ciliated epithelial cells (median [interquartile range]: 1.6 [1.3 to 3.4%] versus 5 [2.2 to 9.8%], p = 0.05) was observed in the BAL fluid (BALF). There was a significant decrease in SP immunoreactivity following ozone exposure (median [interquartile range]: 0.6 [0.05 to 1.2] versus 0.15 [0.08 to 0.18], p < 0.05). A significant inverse correlation was observed between SP immunoreactivity and: (1) percent PMNs and ciliated epithelial cells in the BALF; and (2) percent change in FEV1 following exposure to ozone. These findings indicate that short-term exposure to 0.2 ppm ozone causes epithelial shedding and stimulates subepithelial sensory nerves to release SP into the airways. The release of SP could contribute to bronchoconstriction and subsequent neutrophil infiltration into the airways.
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PMID:Effects of ozone on epithelium and sensory nerves in the bronchial mucosa of healthy humans. 931 18

The substance P (SP)-containing nerves at the deep (DMP) and myenteric (MP) plexuses and the related interstitial cells of Cajal (ICC-DMP and ICC-MP) were immunohistochemically studied in rat and guinea-pig ileum. All the ICC expressed SP-preferred receptor NK1r: the ICC-DMP showed an intense and the ICC-MP a faint NK1r-immunoreactivity(IR). c-kit-labeling confirmed that they were ICC. The SP-IR nerves at the DMP were significantly more numerous in the guinea-pig than in the rat, and more numerous than those at the MP in both animal species. All the ICC-DMP in the guinea-pig and half of them in the rat were close to SP-IR nerves. The ICC-MP were rarely near to SP-IR nerves in either species. The SP-innervation shows interspecies differences at the DMP that imply a different tachykinergic control of the local ICC.
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PMID:Substance P immunoreactive nerves and interstitial cells of Cajal in the rat and guinea-pig ileum. A histochemical and quantitative study. 1040 75

It has previously been shown that high dose of irradiation to the rat abdomen leads to an increased level of substance P (SP) in the duodenum. In the present study the pattern of distribution of NK1 receptors (NK1-R) in rat duodenum after irradiation (5-30 Gy), was examined at the same time-point (7 days) after irradiation, comparisons being made with the distribution of SP-innervation. Immunohistochemical methods were used. In controls, NK1-R-like immunoreactivity (-LI) was detected in epithelial cells, in cells in the region of the intestinal cells of Cajal within the deep muscular plexus (ICC-DMP), in neuronal cells in the myenteric plexus, and variably in granulocytes in the mucosa. Irradiation with 5-10 Gy did not lead to obvious changes in the pattern of NK1-R-LI. After irradiation with the highest doses (25-30 Gy), the mucosa was often gravely damaged, displaying granulation tissue. No epithelial NK1-R-LI was detected in this tissue, but was present in less affected mucosa after these doses. In the region of the ICC-DMP, in the myenteric plexus, and in granulocytes, NK1-R-LI was detected also after high dose irradiation. However, the degree of NK1-R-LI in the region of the ICC-DMP was somewhat lower than seen in controls and after low doses. SP-immunoreactive nerve fibers were present in the regions where NK1-R-LI was detected. These findings support a suggestion that an increased level of SP after irradiation may contribute to the dose-dependent gastrointestinal adverse effects that occur after radiotherapy.
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PMID:Substance P (NK1) receptor in relation to substance P innervation in rat duodenum after irradiation. 1123 Oct 41

Recent studies have demonstrated that intramuscular interstitial cells of Cajal (ICC) are preferential targets for neurotransmission in the stomach. Terminals of enteric motor neurones also form tight, synaptic-like contacts with ICC in the small intestine and colon, but little is known about the role of these cells in neurotransmission. ICC at the deep muscular plexus (ICC-DMP) of the small intestine express neurokinin 1 receptors (NK1R) and internalize these receptors in response to exogenous substance P. We used NK1R internalization as an assay of functional innervation of ICC-DMP in the murine small intestine. Under basal conditions NK1R-like immunoreactivity (NK1R-LI) was mainly observed in ICC-DMP (519 cells counted, 100% were positive) and myenteric neurones. ICC-DMP were closely apposed to substance P-containing nerve fibres. Of 338 ICC-DMP examined, 65% were closely associated with at least one substance P-positive nerve fibre, 32% were associated with at least two, 2% were associated with more than two nerve fibres and 1% with none. After electrical field stimulation (EFS, 10 Hz; 1 min) NK1R-LI was internalized in more than 80% of ICC-DMP, as compared to 10% of cells before EFS. Internalization of NK1R was not observed in myenteric ICC or smooth muscle cells in response to nerve stimulation. Internalization of NK1R-LI was blocked by the specific NK1 receptor antagonist WIN 62577 (1 microm) and by tetrodotoxin (0.3 microm), suggesting that internalization resulted from stimulation of receptors with neurally released neurokinins. These data suggest that ICC-DMP are primary targets for neurokinins released from enteric motor neurones in the intestine.
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PMID:Interstitial cells of Cajal are functionally innervated by excitatory motor neurones in the murine intestine. 1475 97

The tachykinin substance P (SP) acts on the gut muscle coat via its preferred receptor, neurokinin 1 (NK1r). In the mouse ileum, NK1r-immunoreactivity (NK1r-IR) was detected in neurons, in the interstitial cells of Cajal at the deep muscular plexus (ICC-DMP) and the myoid cells of the villi. SP-IR was detected in neurons and varicose nerve fibers, which were especially numerous at the DMP and closely associated with the ICC-DMP. In mice with a mutation in the W locus (ckit mutant animals), innervation is suggested to be normal although few studies have actually tested this hypothesis. Indeed, studies demonstrating ICC-DMP integrity are lacking and whether SP- and NK1r-IR are normal in these animals has not been investigated. Our aim was to perform an immunohistochemical study on the ileum of a strain of heterozygous mice with a mutation in the W locus, the W(e/+) mice, to test this hypothesis. SP-IR nerve fibers were significantly more numerous than in wild type mice; NK1r-IR was clustered on the plasma membrane and also intracytoplasmatic in the neurons, but absent in the ICC-DMP. The richness in SP-IR nerve fibers and the NK1r-IR distribution in the neurons, similar to that of activated cells, might be attempts to compensate for the SP preferred receptor absence at the ICC-DMP. In conclusion, SP content and NK1r expression are noticeably different in c-kit mutants with respect to wild type mice, and probably causing an anomalous tachykininergic control of intestinal motility. Physiological studies on Wmutant mice have to take into account that innervation in this animal model is affected by the c-kit mutation.
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PMID:Substance P and Neurokinin 1 receptor - expression is affected in the ileum of mice with mutation in the W locus. 1679 16


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