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)

1. Intrathecal (i.t.) injections of the (tachykinin) NK1 receptor agonist, substance P methyl ester (SPME; 20 pmol), or the NK2 receptor agonist, neurokinin A (NKA; 20 pmol), substantially decreased the cutaneous mechanical threshold and markedly enhanced the touch-evoked response of posterior biceps femoris-semitendinosus (PBF-ST) spinal flexor motoneurones in decerebrate-spinal rats. This cutaneous mechanical reflex allodynia was prevented by pretreatment with the NK1 antagonist RP 67580 (2.28 nmol, i.t.) and the NK2 antagonist MEN 10376 (0.7 nmol, i.t.), respectively. 2. Electrical stimulation of the sural nerve at C fibre strength or cutaneous application of the irritant, mustard oil, produced prolonged cutaneous mechanical allodynia in PBF-ST motoneurones (15 min and > 1 h, respectively). Pretreatment with RP 67580 but not MEN 10376 prevented this, but when RP 67580 was administered 25 min after the application of mustard oil, the established hypersensitivity of the flexor motor reflex was not reversed. The enantiomer of RP 67580, RP 68651 was without effect. 3. Injection of bradykinin (60 microM, 80 microliters) into the gastrocnemius muscle increased the cutaneous mechanical hypersensitivity of PBF-ST flexor motoneurones for 40-50 min. MEN 10376, but not RP 67580, prevented this, but only when administered prior to the bradykinin injection. 4. These results suggest that the induction, but not the maintenance, of cutaneous mechanical allodynia in flexor motoneurones is NK receptor dependent, with cutaneous C fibre conditioning inputs acting via NK1 and muscle C fibre conditioning inputs via NK2 receptor subtypes.
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PMID:Involvement of neurokinin receptors in the induction but not the maintenance of mechanical allodynia in rat flexor motoneurones. 747 37

The selective NK2 agonist [Lys5-MeLeu9,Nle10]NKA(4-10) markedly stimulated [3H]inositol monophosphate (PI1) formation in prisms from the rat urinary bladder. This response was blocked by the NK2 antagonist SR 48968. Senktide (NK3 agonist) was inactive. Septide, a short SP analogue, and the NK1 agonists [Pro9]SP and [Sar9,Met(O2)11]SP also stimulated [3H]IP1 formation and several NK1 tachykinin antagonists (RP 67580, CP 96345, GR 82334, and [D-Pro9,t beta-BPr10,Trp11]SP) were more potent in blocking the septide than the [Pro9]SP response. GR 82334 was the most discriminative. SR 48968 (10(-6) M shifted the [Pro9]SP dose-response curve but did not modify the septide dose-response curve. Septide had a low affinity for [3H][Pro9]SP binding sites, suggesting further that septide and NK1 agonists act on different receptors. Finally, both [Pro9]SP and [Sar9,Met(O2)11]SP blocked the septide-evoked response, acting as partial agonists at the septide-sensitive tachykinin receptors.
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PMID:Involvement of septide-sensitive tachykinin receptors in inositol phospholipid hydrolysis in the rat urinary bladder. 747 88

In vitro and in vivo test systems were used to compare the biological activities of substance P and the neurokinins A and B with those of a newly isolated substance P-like acidic peptide, PG-SPI (pGlu-Pro-Asn-Pro-Asp-Glu-Phe-Phe-Gly-Leu-Met-NH2). On nearly all the isolated smooth muscle preparations tested, PG-SPI appeared only slightly more potent than SP, but on guinea pig trachea it was 50 times more potent. The in vitro spasmogenic effect of PG-SPI on guinea pig trachea was inhibited by the NK1 receptor antagonist, CP 96,345. In in vivo tests, intracerebroventricularly injected PG-SPI was about 20 times more potent than SP in inhibiting gastric acid secretion and emptying in rats. Tests with antagonists showed that CP 96,345 reduced PG-SPI-induced inhibition of gastric emptying and the NK2 receptor antagonist, MEN 10,376, sharply blocked PG-SPI-induced inhibition of gastric acid secretion. These findings fit poorly into the current classification of tachykinin receptors and suggest that the acidic substance P-like peptide is a valuable tool for studying the functional role of other tachykinin receptor subtypes.
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PMID:Parallel bioassay of PG-SPI, an amphibian acidic SP-like peptide, mammalian basic substance P, and neurokinins A and B on in vitro and in vivo test systems. 747 92

To determine whether tachykinins induce gelatinase production by guinea pig alveolar macrophages (AM), and to characterize the mechanism involved, we incubated AM with substance P (SP), neurokinin A (NKA), or the NH2-terminal fragment of SP, SP(1-7). The effects of increasing concentrations of selective NK1 and NK2 agonists on tachykinin-induced gelatinase production were also evaluated, as were the effects of a selective NK2 antagonist. Gelatinase activity in conditioned culture media (CCM) was assessed by zymography and quantified by image analysis. SP increased 92-kDa gelatinase activity in CCM of AM in a concentration-dependent manner, with a maximum increase at 10(-4) M. NKA, the NH2-terminal fragment of SP, and an NK1-selective agonist had no effect. In contrast, a selective NK2 agonist induced a concentration-dependent increase in gelatinase activity. The increase in this activity induced by SP and the selective NK2 agonist was inhibited by a selective NK2 antagonist. We conclude that SP induces gelatinase production by AM through NK2 receptor activation. The release of gelatinase may constitute one mechanism through which SP contributes to the epithelial lesions observed in bronchial hyperreactivity and asthma.
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PMID:Tachykinins induce gelatinase production by guinea pig alveolar macrophages: involvement of NK2 receptors. 749 82

We have characterized the receptor(s) mediating contraction and relaxation produced by tachykinins in the rabbit isolated jugular vein. The tachykinin NK1 receptor-selective agonists septide and [Pro9]substance P produced concentration-dependent contractions which were potentiated by either the removal of the vascular endothelium (Emax = +106% and +72%, respectively) or by pretreatment with L-nitroarginine (100 microM; 60 min before) (Emax = +123% and +71%, respectively). The tachykinin NK1 receptor-selective antagonist, (+/-)-CP-96,345 ([2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2,2,2]octan-3-amine]) (10-300 nM) competitively antagonized septide (pKB = 9.0) with 10-fold greater potency than [Pro9]substance P (pKB = 8.0). In preparations with intact endothelium both septide and [Pro9]substance P (from 0.1 to 100 nM) relaxed the noradrenaline-(10 microM) induced tone, and their effects were markedly reduced by (+/-)-CP-96,345 (100 nM). In noradrenaline-precontracted veins L-nitroarginine (100 microM) reversed the tachykinin-induced vasodilation into a contraction, providing evidence for the involvement of nitric oxide in this response. The tachykinin NK3 and NK2 receptor-selective agonists senktide and [beta Ala8]neurokinin A-(4-10) were either ineffective, or produced small effects antagonized by (+/-)-CP-96,345 (100 nM), respectively. In conclusion, tachykinin NK1 receptors mediate both tachykinin-induced contraction and relaxation in the rabbit jugular vein. This preparation, deprived of the endothelium or pretreated with L-nitroarginine, is suitable for evaluating tachykinin agonists or antagonists.
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PMID:Tachykinin NK1 receptors mediate both vasoconstrictor and vasodilator responses in the rabbit isolated jugular vein. 749 15

The regulatory peptide substance P has been implicated in the development and persistence of inflammatory synovitis. The authors used quantitative in vitro receptor autoradiography to compare synovial binding of 125Iodine-Bolton Hunter-labeled substance P ([125I]BH-SP) in rats and humans and between uniflamed and persistently inflamed synovium. [125I]BH-SP binding to microvascular endothelium paralleled the distribution of substance P-immunoreactive nerves and had characteristics of the neurokinin (NK) 1 class of tachykinin receptor. Specific binding was inhibited by the selective NK1 receptor antagonist, FK888, and the dual NK1/NK2 receptor antagonist FK224, with Hill coefficients near unity. FK888 was > 1000 times and FK224 > 10 times more potent at inhibiting binding in human compared with rat synovium. Synovium from patients and rats with chronic arthritis contained heterogeneously distributed inflammatory cell infiltrates. For the 10 microvessels with the densest [125I]BH-SP binding in each section, no significant differences in binding density, affinity, or Ki values for substance P, FK888 or FK224 were found between synovium from naive and monoarthritic rats, nor between that from patients with rheumatoid arthritis or osteoarthritis. However, in both rat and human specimens, microscopic examination suggested that microvascular [125I]BH-SP binding in intensely infiltrated regions of synovium was less dense than in adjacent, less infiltrated areas. It was concluded that NK1 receptors are similarly distributed in rat and human synovium but show major differences in selectivity for antagonists such as FK888. NK1 receptors in synovium may mediate proinflammatory actions of locally released substance P; defective neurovascular regulation may contribute to the persistence of chronic arthritis.
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PMID:Microvascular substance P binding to normal and inflamed rat and human synovium. 750 2

We examined an endogenous substance causing cough in awake guinea pigs. An intraperitoneal injection of phosphoramidon, a selective inhibitor of neutral endopeptidase (E.C. 3.4.24.11), caused cough in a dose-dependent fashion for approximately 40 min. At a dose of 3 x 10(-3) mol/kg, phosphoramidon caused a total of 11.6 +/- 1.4 coughs in 40 min. Phosphoramidon (3 x 10(-3) mol/kg)-induced cough was significantly inhibited by systemic pretreatment with capsaicin (p < 0.01). Aerosols of FK 888 (1 min), a specific inhibitor of substance P (NK1) receptor, inhibited phosphoramidon (3 x 10(-3) mol/kg)-induced cough in a dose-dependent fashion with complete inhibition at a dose of 10(-5) M. Likewise, aerosols of FK 224 (10(-5) M; 1 min), another inhibitor of NK1 and NK2 receptors, or lidocaine (4%, 1 min) significantly inhibited phosphoramidon (3 x 10(-3) mol/kg)-induced cough (p < 0.01). Furthermore, aerosols of FK 888 (10(-5) M; 1 min) significantly inhibited cough induced by cigarette smoke in awake guinea pigs (p < 0.01). These results suggest that substance P released from sensory nerves in the airway may be an endogenous substance causing cough and the substance P antagonist may be the drug for treatment of cough in respiratory disease.
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PMID:Evidence for substance P as an endogenous substance causing cough in guinea pigs. 750 93

The present study evaluated the effect of tachykinin agonists, selective for different neurokinin (NK) receptors, on alcohol intake in genetically selected, Sardinian alcohol-preferring rats. Tachykinins were given by intracerebroventricular injection just before access to fluids. In rats offered both water and 8% ethanol 2 h/day, the NK3 selective agonists [Asp5.6,MePhe8]substance P(5-11), Suc[Asp6,MePhe8]substance P(6-11), and [MePhe7]neurokinin B markedly suppressed alcohol intake. The NK1 selective agonist [Sar9,Met(O2)11]substance P and the NK2 selective agonist GR 64349 did not At doses that inhibited alcohol intake, the NK3 agonists did not modify water intake; total fluid intake was significantly reduced only following 500 ng/rat of [Asp5.6,MePhe8]substance P(5-11). When rats were given a longer access to fluids (8% alcohol for 2 h, but water for 4 h), again, NK3 agonists suppressed alcohol intake, but not total fluid intake. Moreover, NK3 agonists did not modify solid food intake in food-deprived rats, nor water intake in water-deprived rats, when alcohol was not available. These findings indicate that NK3 agonists inhibit alcohol intake in Sardinian alcohol-preferring rats and that their effect is behaviorally selective. They also suggest that central NK3 receptors may be involved in alcohol intake control in rats.
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PMID:Selective agonists at NK3 tachykinin receptors inhibit alcohol intake in Sardinian alcohol-preferring rats. 750 13

The selective agonists of tachykinin NK1, NK2 and NK3 receptors, respectively [Pro9]substance P, [Lys5,MeLeu9,Nle10]neurokinin A-(4-10) and senktide, stimulated phosphoinositide breakdown in slices of the guinea pig ileum. This was also the case with septide which has recently been found to act on a new type of tachykinin receptors in this tissue. The NK1, NK2 and septide-evoked responses were completely antagonized in the combined presence of (+/-)-CP-96,345 and MEN 10,376 which are potent and selective antagonists of tachykinin NK1 and NK2 receptors respectively in the guinea pig ileum. Like senktide, other available NK3 receptor agonists, such as [MePhe7]neurokinin B, [MeVal7]neurokinin B, [Pro7]neurokinin B and DiMe-C7, stimulated phosphoinositide hydrolysis in either the absence or combined presence of (+/-)-CP-96,345 and MEN 10,376, although senktide was the most potent. Therefore, following the blockade of tachykinin NK1, NK2 and septide-sensitive receptors, the accumulation of inositol monophosphate appears to be a valuable, rapid and sensitive bioassay for determining the activity of NK3 receptor agonists and putative NK3 receptor antagonists.
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PMID:A new selective bioassay for tachykinin NK3 receptors based on inositol monophosphate accumulation in the guinea pig ileum. 750 59

Neuropeptides exert a variety of modulatory effects on inflammatory cellular responses. In order to investigate further activities of these cytokines on mechanisms in inflammatory processes, we determined the ability of substance P to promote human fibroblast chemotaxis. Cell migration was measured by two different assay types in modified Boyden chambers. Substance P was found to be a potent chemoattractant for human fibroblasts in vitro, eliciting a concentration-dependent migratory response. In further investigations we tested the chemoattractant potency of the fragments substance P-(1-4) and substance P-(3-11). As only the C-terminal analog promoted migratory responses, we suggest that the chemotactic responsiveness is largely encoded by the C-terminus of the neuropeptide, which is known to be active on neurokinin receptors. Involvement of neurokinin receptors of type 1 in the chemotactic response to substance P was indicated by fibroblast migration toward optimal concentration of a selective NK1 receptor agonist but not a NK2 receptor agonist. The observed ability of human fibroblasts to respond chemotactically to substance P elucidated another proinflammatory activity of this neuropeptide.
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PMID:Stimulation of the chemotactic migration of human fibroblasts by substance P. 750 58


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