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)

Although abundant evidence suggests a major role for substance P (SP) and other neurokinins (NK) in the transmission of nociceptive information, it is not known whether the various NK receptor classes are differentially located in the substantia gelatinosa of the spinal cord where primary afferent fibres mostly terminate. In order to investigate this issue, we studied the effects of unilateral dorsal rhizotomy on binding of 125I-Bolton-Hunter-SP, (2-[125I]iodohistidyl1)-neurokinin A, and 125I-Bolton-Hunter-eledoisin as respective radioligands for the NK-1, NK-2 and NK-3 receptor sub-types. Seven, 14, 21 and 28 days following unilateral lumbosacral dorsal horn deafferentiation, NK receptor binding parameters were evaluated using quantitative receptor autoradiography. Rhizotomy produced an increase in the densities of NK-1, NK-2 and NK-3 binding sites in the superficial laminae of the dorsal horn. Increases were maximal at 14 days, post-operatively, for both NK-1 and NK-2 sites; slight recovery being observed thereafter. For NK-3 sites, unilateral rhizotomy induced a progressive increase in binding without evidence of recovery over time, at least up to 28 days post-lesion. NK-1 receptor binding parameters around the central canal and in the ventral horn were not affected by the dorsal rhizotomy. These data suggest that all 3 NK receptor classes are located post-synaptically to afferent fiber terminals in laminae I, II and X of the dorsal horn of the spinal cord.
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PMID:Effects of dorsal rhizotomy on neurokinin receptor sub-types in the rat spinal cord: a quantitative autoradiographic study. 171 14

Following the recent discovery of a new substance P (SP) competitive pancreatic acini cell receptor antagonist containing a reduced peptide bond in place of the C-terminal peptide bond, a new series of full chain and short chain (heptapeptide and hexapeptide) substance P analogues have been prepared in which one of the C-terminal-region peptide bonds has been replaced by CH2NH or CH2O groups. They were compared for their ability to recognize NK1 and/or NK2 tachykinin receptor binding sites on guinea pig ileum and rat duodenum smooth muscle preparations, respectively. It was found that all full sequence SP pseudopeptides were agonists with much reduced bioactivity in both tested systems and, in addition, [Gly9 psi(CH2NH)Leu10,Leu11]SP was found to be a relatively selective agonist for NK1 binding sites. Substitution of leucine at position 11 of SP heptapseudopeptides with phenylalanine generated a pseudopeptide with weak agonist activity when Gln at position 5 was replaced by D-Phe, or antagonists when this residue was replaced by D-Nal or D-Cpa. [Leu10 psi(CH2NH)Leu11]SP-(6-11) with Gln at position 6 substituted by D-Phe was a relatively stronger antagonist in both assay systems. These results suggest that, as with several other peptide systems of late, manipulation of the peptide bonds in SP can produce receptor antagonists which in some cases approach the potency of the classic spantide series and, furthermore, that the approach might be used to induce NK receptor specificity in both agonist and antagonist analogs.
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PMID:New reduced peptide bond substance P agonists and antagonists: effects on smooth muscle contraction. 172 44

As a means of evaluating the role of neurokinins (NKs) in spinal function, the present study examines the quantitative autoradiographic distribution in the rat spinal cord of [125I]Bolton-Hunter-substance P, (2-[125I]iodohistidyl1)-neurokinin A and [125I]Bolton-Hunter-eledoisin as respective radioligands for NK-1, NK-2 and NK-3 receptors. These putative NK receptor sub-types are clearly differentially distributed at the various levels of the spinal cord. NK-1 sites represent the most abundant population of spinal NK receptors. They are most concentrated in the dorsal and ventromedial borders of the dorsal horn, the intermediolateral nucleus of the thoracic cord and the phrenic motor nucleus in the cervical ventral horn. NK-2 and NK-3 sites are also present in the spinal cord, although in much lower quantities than NK-1 sites. NK-2 sites are mostly found along the dorsal and ventromedial borders of the dorsal horn, in a narrow band connecting the two lateral horns of the thoracic cord, around the central canal of the lumbar and sacral segments and lamina IX of the cervical ventral horn. NK-3 sites are most dense in the dorsal border of the dorsal horn, with moderate amounts in the lateral horn of the thoracic cord and around the central canal of lumbar and sacral segments. The differential distribution of these 3 classes of NK sites in the spinal cord suggests that each NK receptor sub-type could mediate specific sensory, autonomic and/or motor functions at the spinal level.
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PMID:Quantitative autoradiographic distribution of multiple neurokinin binding sites in rat spinal cord. 215 84

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 data presented in this paper demonstrate a new substance P (SP) binding site that is expressed on human monocytes. The apparent dissociation constant (Kd) for binding of 125I-labeled Bolton Hunter-SP (125I-BH-SP) to the receptor on monocyte membranes is 2.24 +/- 0.9 x 10(-7) M and the maximum binding capacity (Bmax) is 4.7 +/- 0.5 pmol/mg membrane protein. It could be excluded that this receptor is one of the known neurokinin (NK) type of receptors on the basis of binding characteristics for NK1, NK2, and NK3 agonists. Moreover, we demonstrate that the binding site is neither the bombesin receptor nor the serpin enzyme complex receptor nor the FMLP receptor. The order of potency for inhibition of 125I-BH-SP binding to the receptor on monocyte membranes is NK1 antagonist [D-Pro2,D-Trp7,9]SP > SP > NK3 agonist [MePhe7]SP > bombesin. Cross-linking studies with disuccinimidylsuberate, followed by SDS-PAGE analysis, revealed that 125I-BH-SP is specifically bound to a membrane protein with an apparent molecular mass of 47 kDa. At a functional level, SP induces the activation of MAP kinase in human monocytes. The ED50 for activation of MAP kinase positively correlated (r = 0.999, p < 0.0005) with the apparent affinity of the ligands applied in the 125I-BH-SP displacement studies. From these results, we conclude that this SP binding site on monocytes is a non-NK receptor protein that is functionally linked to the activation of MAP kinase.
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PMID:Monocytes express a non-neurokinin substance P receptor that is functionally coupled to MAP kinase. 751 35

The neurokinin receptors responsible for transducing the airway obstruction resulting from capsaicin infusion were defined in the tracheally perfused guinea pig lung. In this lung preparation, buffer is perfused via the trachea and allowed to exit the lung through numerous small holes in the pleural surface; airway obstruction is monitored as the backpressure (Pao) generated at a constant perfusion flow rate. Infusion of the specific NK1 receptor agonist, Sar-9 Met02(11) substance P, resulted in an increase in Pao; this effect was prevented by the NK1 receptor antagonist CP 99,994 but not by the NK2 receptor antagonist SR 48,968. Infusion of the specific NK2 receptor agonist Nle10-neurokinin A 4-10 resulted in an increase in Pao; this effect was prevented by the NK2 receptor antagonist SR 48,968 but not by the NK1 receptor antagonist CP 99,994. In the absence of NK receptor antagonists, infusion of capsaicin resulted in a significant increase in Pao, 31 +/- 4 cm H2O. In the presence of the NK1 receptor antagonist, the capsaicin response was not diminished, but in the presence of the NK2 receptor antagonist, the Pao response diminished to only 10 +/- 2 cm H2O, p < 0.001. These data indicate that when capsaicin is presented to the epithelial surface of the lung the resulting airway obstruction is mediated predominantly by NK2 receptor stimulation.
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PMID:Capsaicin-induced airway obstruction in tracheally perfused guinea pig lungs. 751 95

Capsaicin, instilled intravesically in normal, unanesthetized rats induced a concentration-dependent bladder hyperactivity, which could be abolished by hexamethonium, given intra-arterially near the bladder, or by morphine administered intrathecally. The effect was reversible and could be repeated. The NK-2 receptor selective antagonist SR 48,968 and the nonselective NK receptor antagonist spantide, given intra-arterially near the bladder, which by themselves, in the concentrations used, did not affect cystometric parameters, both counteracted the capsaicin-induced hyperactivity, whereas the NK-1 receptor selective antagonist RP 67,580 failed to do so. Blockade of tachykinin receptors in the urinary bladder does not seem to produce changes of the micturition reflex associated with bladder filling in the conscious rat. However, tachykinins released from capsaicin-sensitive nerves by various stimuli may, through stimulation of NK-2 receptors, lower the threshold for initiation of the micturition reflex. In the rat, intravesical capsaicin may be a suitable model for studies of afferent activity caused by stimuli releasing peptides from sensory nerves in the bladder, thereby provoking bladder hyperactivity.
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PMID:Capsaicin-induced bladder hyperactivity in normal conscious rats. 751 84

The tachykinins, substance P (SP) and neurokinins A (NKA) and B (NKB), have been identified in the respiratory tract and implicated in mediating neurogenic inflammation of the airways. To the extent that these neuropeptides may be involved in the pathogenesis of asthma, a condition associated with hyperplasia of airway smooth muscle (ASM), we examined the mitogenic effects and mechanisms of action of tachykinins in cultured rabbit ASM cells. SP was found to elicit dose-dependent (10(-14) to 10(-4) M) stimulation of ASM cell proliferation, with a mean (+/- SE) maximal increase in cell number of 169 +/- 6.1% of control. In contrast, NKA and NKB had little and no effect on ASM cell growth, respectively. Because SP is nonselective in its binding to the tachykinin receptors, to identify the specific NK receptor subtype(s) mediating the promitogenic action of SP, in separate studies we found that 1) the NK1-receptor-specific agonist, [beta-Ala4, Sar9, Met(O2)11]SP-(4-11) induced stimulation of ASM cell growth similar in magnitude to that elicited by SP; 2) in contrast, neither the NK1- nor NK2-receptor-specific agonists, [beta-Ala8]NKA-(4-10) and [MePhe7]NKB, respectively, had any effect on ASM cell growth; and 3) the promitogenic action of SP was inhibited by the NK1-receptor antagonist, GR-82,334. Moreover, in extended experiments, we found that the phospholipase C and phospholipase A2 inhibitors, neomycin and quinacrine, respectively, each inhibited SP-induced ASM cell proliferation by approximately 45%. Collectively, these observations provide new evidence that the tachykinin SP induces ASM cell proliferation, and that this action is mediated by transmembrane signaling coupled to selective activation of the NK1 receptor.
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PMID:Tachykinin regulation of airway smooth muscle cell proliferation. 757 67

1. This study investigates the effects of capsaicin-induced depletion of sensory neuropeptides and of neurokinin1 (NK1) receptor blockade on delayed-type hypersensitivity (DTH)-induced changes of vascular permeability in the small intestine of the mouse. 2. The DTH reaction in the small intestine was elicited by dinitrofluorobenzene (DNFB)-contact sensitization followed by oral dinitrobenzene sulphonic acid (DNBS) challenge. To assess vascular leakage the accumulation of the plasma marker, Evans blue (EB), was measured 2, 24 and 48 h after the challenge. 3. The small intestinal DTH reaction was characterized by a significant increase in vascular permeability 24 h after the challenge of previously sensitized mice when compared to vehicle-sensitized mice (P < 0.05, ANOVA). Capsaicin-induced depletion of sensory neuropeptides, two weeks before the sensitization, completely inhibited the DTH-induced increase in small intestinal vascular permeability at 24 h (P < 0.05, ANOVA). Vehicle/control: 108.2 +/- 8.6 ng EB mg-1 dry weight; vehicle/DTH 207.8 +/- 25.1 ng EB mg-1 dry weight; capsaicin/control: 65.8 +/- 11.9 ng EB mg-1 dry weight; capsaicin/DTH: 84.3 +/- 7.6 ng EB mg-1 dry weight. 4. The tachykinins, substance P and neurokinin A (1.5 to 50 x 10(-11) mol per mouse, i.v.), induced an increase in vascular leakage in the small intestine of naive mice. The specific NK1 receptor antagonist, RP67580 (10(-9) mol per mouse, i.v.) was the most effective in reducing the substance P-induced plasma extravasation when compared with other NK receptor antagonists, FK224 and FK888. 5. Treatment of DNFB-sensitized mice with RP67580 (10-9 mol per mouse, i.v.) immediately before and 1 h after the DNBS challenge resulted in a significant reduction of the DTH-induced increase in vascular permeability at 24 h (vehicle/control: 107.5 +/- 8.8 ng EB mg-1 dry weight; RP67580/control:95.4 +/- 5.4 ng EB mg-1 dry weight; vehicle/DTH: 206.6 +/- 22.6 ng EB mg-1 dry weight; RP67580/DTH:132.6 +/- 13.6 ng EB mg-1 dry weight, P<0.05, ANOVA).6. These results suggest that sensory nerves are involved in the development of small intestinal DTH reactions in the mouse. NK1 receptors could play an important role in the initiation of the DTH-induced changes in vascular leakage.
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PMID:Delayed-type hypersensitivity-induced increase in vascular permeability in the mouse small intestine: inhibition by depletion of sensory neuropeptides and NK1 receptor blockade. 760 52

We have studied the effect of a novel tachykinin, neuropeptide gamma (NP gamma) on small intestinal motility in the rat. Experiments were done in vitro on longitudinal muscle strips of duodenum, and in vivo on the migrating myoelectric complex (MMC) of the small intestine. In vitro, contractile effects of NP gamma were compared with those of a selective neurokinin 1 (NK1) receptor agonist, substance P methyl ester (SPME), and a selective neurokinin 2 (NK2) receptor agonist, Nle10-NKA(4-10)(NleNKA). NP gamma, SPME and NleNKA caused concentration-dependent contractions (P < 0.001). NP gamma was eight-fold more potent than NleNKA, and 118-fold more potent than SPME. Contractile responses to NP gamma were reduced by hexamethonium (P < 0.01) and atropine (P < 0.05). The non-selective NK receptor antagonist spantide I only slightly reduced the contractile response to NP gamma, as did the selective NK1 antagonist GR 82,334, and the selective NK2 antagonist L-659,877 and MEN 10,376. In vivo, effects of NP gamma on the MMC were compared with those of the natural tachykinins substance P (SP) and neurokinin A (NKA). NP gamma disrupted the MMC and induced irregular spiking in a dose-dependent manner from 25 to 100 pmol kg-1 min-1 i.v. (P < 0.05). The effect of NP gamma was more prominent than that of NKA at equal doses, while SP had no effect. Our findings show that NP gamma exerts potent stimulatory effects on small intestinal motility, most likely mediated directly via distinct NK receptors on smooth muscle cells, but also indirectly via a cholinergic link.
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PMID:Intestinal motility responses to neuropeptide gamma in vitro and in vivo in the rat: comparison with neurokinin 1 and neurokinin 2 receptor agonists. 797 23


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