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)

1. The effect of removal of the longitudinal muscle-myenteric plexus (LM-MP) and/or indomethacin (10 microM) on the response to the tachykinin NK-2 receptor selective agonist, [beta Ala8]NKA(4-10), or to the NK-3 receptor selective agonist, senktide, was investigated by measuring mechanical activity (isotonic recording) of circular muscle (ring preparation) of the guinea-pig ileum. 2. Indomethacin (10 microM) increased the percentage of ileal rings displaying spontaneous activity, either intact or LM-MP-free. The response to senktide (10 nM and 1 microM) was lower in LM-MP-free than in intact ileal rings, either in the absence or presence of indomethacin. The response to a low concentration (10 nM) of [beta Ala8] NKA (4-10) was enhanced in LM-MP-free rings and by indomethacin. 3. In intact ileal rings, the response to senktide was unaffected by atropine (3 microM) alone or by the tachykinin NK-2 receptor antagonist MEN 10,376 (10 microM) alone while it was reduced by the combined administration of the two antagonists. The response to senktide was greatly reduced by tetrodotoxin (TTX, 1 microM). Senktide-induced contractions (10 nM) were also reduced by the blocker of N-type voltage-sensitive calcium channels, omega-contoxin (CTX, 0.1 microM). 4. In about 30% of preparations tested, an inhibitory response (decrease in spontaneous activity) to 10 nM senktide, was disclosed in CTX-treated intact ileal rings. This inhibitory effect was TTX-sensitive. 5. In LM-MP-free ileal rings, the response to senktide was abolished or reduced by atropine and MEN 10,376, alone or in combination, and was also reduced or abolished by TTX and CTX. 6. The response to [beta Ala8]NKA (4-10) was inhibited by MEN 10,376, in both intact and LM-MP-free ileal rings while it was unaffected by atropine, TTX or CTX. 7. These results indicate that indomethacin pretreatment induces a regular background activity for studying the motor response to tachykinins in the circular muscle of the ileum, probably by blocking the formation of relaxant prostanoids. A further increase in sensitivity to direct smooth muscle stimulation (NK-2 receptor agonist) can be obtained by removal of the LM-MP. The response to NK-3 receptor stimulation is diminished but not abolished by removal of the LM-MP, suggesting that NK-3 receptors are located on neuronal bodies of myenteric neurons, but possibly also at other sites (possibly, nerve terminals).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of longitudinal muscle-myenteric plexus removal and indomethacin on the response to tachykinin NK-2 and NK-3 receptor agonists in the circular muscle of the guinea-pig ileum. 751 89

Functional NK-1 (substance P) receptors have been demonstrated previously on astrocytes from primary newborn rat brain cultures and human astrocytoma cells lines by specific [125I]-Bolton Hunter substance P (SP) binding and by SP-induced phosphoinositol turnover. In addition, these cells have been shown to release cytokines upon stimulation with interleukin-1 (IL-1) and lipopolysaccharide (LPS). Since SP has also been shown to induce cytokine release from rat glial cells, this neuropeptide may contribute to the pathophysiology of neuronal inflammation in humans by stimulating cytokine production in the brain. We, therefore, explored whether SP could induce U-373 MG human astrocytoma cells, via specific NK-1 receptor activation, to secrete interleukin-6 (IL-6), a cytokine implicated as a key mediator of immune and inflammatory responses. SP stimulated IL-6 production in a concentration-dependent manner with an MC50 (concentration inducing 50% of the maximum response) of 45 nM. IL-6 was detected in the cell culture supernatant fluids 2 h post stimulation and secretion peaked at 12 h. SP induced IL-6 secretion was not mediated by IL-1 since neutralizing anti-IL-1 (alpha and beta) antibody treatment had no effect on the SP response. The selective NK-1 receptor agonist, [Sar9, Met(O2)11]-SP, was comparably effective to SP in stimulating IL-6 secretion; however, selective NK-2 and NK-3 receptor agonists were 250-500-fold less effective. In addition, the non-peptide NK-1 receptor antagonist, (+/-)CP-96,345, inhibited SP (Ki = 4 nM), but not IL-1-induced IL-6 release. These selectivity and specificity studies confirmed the presence of functional NK-1 type receptors linked to IL-6 release. The results of this study support a role for SP as a modulator of immune and/or inflammatory processes in the human CNS.
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PMID:Interleukin-6 secretion from human astrocytoma cells induced by substance P. 751 75

Substance P- and opioid peptide-immunoreactive nerve terminals functionally interact in the spinal cord as two opposing systems in the regulation of the nociceptive pathway. In order to determine how SP-ergic system adapts to chronic opioid receptor blockade, the effects of naltrexone on SP level, SP receptor and the second messenger system coupled to the SP receptor were examined in the rat spinal cord. Male Sprague-Dawley rats were treated with naltrexone or vehicle for seven days by constant minipump infusion. Animals were sacrificed on day 8, spinal cords rapidly removed, segmentally sectioned and used to determine SP and inositol 1,4,5-trisphosphate [ins(1,4,5)P3] tissue contents, and to examine the regulation of their respective receptors in in vitro receptor binding assays. Following chronic naltrexone treatment, SP content in the lumbosacral segment of the spinal cord was increased by 53% over matched control values. The binding capacity (Bmax) of SP receptors, determined using [125I]BHSP, in lumbosacral synaptosomal membranes was significantly increased by 92%, but the binding affinity (Kd) remained unchanged. In addition, the concentration of [Sar9, Met(O2)11]SP, an NK-1 receptor-specific agonist, required to inhibit half of [125I]BHSP binding (IC50) in lumbosacral synaptosomal membranes was significantly decreased, but the IC50s for SP, the endogenous ligand for the SP receptor, and [Pro7]NK B, an NK-3 receptor-specific agonist, were unaltered by chronic blockade of opioid receptors. The data suggest that although naltrexone does not directly interact with tachykinin receptors, it acts indirectly on SP-ergic neurons to cause a change in the apparent affinity of NK-1 receptor (as reflected by a change in IC50 value). Formation of cellular ins(1,4,5)P3 in the lumbosacral cord, quantified by a highly sensitive and selective radioreceptor assay, was significantly increased by 34% relative to matched controls. A time course study indicated that increases in ins(1,4,5)P3 contents over the time studied corresponded qualitatively with increases in SP level in the lumbosacral cord. With [3H]ins(1,4,5)P3 as a ligand, Scatchard analyses of the concentration dependent saturation curves showed that the density of intracellular ins(1,4,5)P3 receptors was also increased by 119%, with no change in binding affinity. The data suggest that ins(1,4,5)P3 formation, possibly coupled to functional SP receptor activation, and ins(1,4,5)P3 receptors, which mediate ins(1,4,5)P3-induced alterations in intracellular Ca2+ flux, are increased in the lumbosacral cord by chronic blockade of opioid receptors. Taken together, the data support the concept of a role for endogenous opioids in the regulation of SP receptor activity in the spinal cord.
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PMID:Modulation of substance P-ergic system in the rat spinal cord by an opioid antagonist. 751 75

The in vivo pharmacological profiles of the selective tachykinin NK1 receptor agonists, [Sar9,Met(O2)11]substance P and GR 73632, were examined in gerbils. Both agonists induced a pronounced chromodacryorrhea following intravenous injection which was stereoselectively antagonised by the tachykinin NK1 receptor antagonist, CP-99,994, but not by its inactive enantiomer, CP-100,263, or the rat-selective tachykinin NK1 receptor antagonist, RP 67,580. In contrast, chromodacryorrhea was not observed following intravenous injection of the selective tachykinin NK2 receptor agonist, [beta-Ala8]neurokinin A-(4-10), or the selective tachykinin NK3 receptor agonist, senktide. These results suggest that [Sar9,Met(O2)11]substance P-induced chromodacryorrhea results from activation of peripheral tachykinin NK1 receptors. Repetitive hind paw tapping was also observed in gerbils but only following intracerebroventricular injection of [Sar9,Met(O2)11]substance P or GR 73632. Furthermore, GR 73632-induced hind paw tapping was significantly attenuated by co-administration of the peptide tachykinin NK1 receptor antagonist, GR 82334, or intravenous injection of CP-99,994. Thus, in contrast to chromodacryorrhea, repetitive hind paw tapping may result from activation of central tachykinin NK1 receptors.
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PMID:Chromodacryorrhea and repetitive hind paw tapping: models of peripheral and central tachykinin NK1 receptor activation in gerbils. 751 50

1. The involvement of neurokinins in the non-cholinergically-mediated contractile response induced by stimulation of 5-HT3 and 5-HT4 receptors has been examined in the longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum. 2. The 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT), showed a lower potency in this preparation than the more selective 5-HT4 receptor agonist 5-methoxytryptamine. The effect of both drugs was markedly reduced by atropine. 3. Substance P (SP) and neurokinin B (NKB) produced biphasic concentration-response curves in the preparation. Neurokinin A (NKA), the NK1 receptor agonist, [Sar9,Met(O2)11]SP and the NK3 receptor agonist, senktide yielded monophasic concentration-response curves. 4. After desensitization of the NK1 receptor with SP or [Sar9,met(O2)11]SP, in the presence of atropine, the contractile response to 2-methyl-5-HT was entirely blocked. Desensitization of NK3 receptors with NKB, also in the presence of atropine, fully suppressed the 5-HT4 receptor-mediated contraction evoked by 5-methoxytryptamine. 5. In preparations prelabelled with [3H]-choline, SP produced a concentration-dependent increase in tritium overflow, an index of [3H]-acetylcholine release, while an inverse relationship was found with NKB. At low neurokinin concentrations, the releasing effect of NKB was much more marked. 6. It is suggested that in the response to 5-HT3 receptor stimulation, there is a role for SP and acetylcholine. NKB appears to be preferentially involved in the release of acetylcholine elicited by stimulation of 5-HT4 receptors.
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PMID:Involvement of neurokinins in the non-cholinergic response to activation of 5-HT3 and 5-HT4 receptors in guinea-pig ileum. 751 54

1. Exogenous tachykinins modulate cholinergic neurotransmission in rabbit and guinea-pig airways. We have investigated the effect of selective tachykinin receptor agonists and antagonists on cholinergic neurotransmission evoked by electrical field stimulation (EFS) of bronchial rings in rabbit, guinea-pig and human airways in vitro to assess which type of tachykinin receptor is mediating this facilitatory effect. 2. Bronchial rings were set up for isometric tension recording. Contractile responses to EFS (60 V, 0.4 ms, 2 Hz for 10 s every min) and exogenous acetylcholine (ACh) were obtained and the effects of selective tachykinin agonists and antagonists were investigated. 3. In rabbit bronchi the endogenous tachykinins, substance P (SP) and neurokinin A (NKA) (10 nM) potentiated cholinergic responses to EFS (by 287.6 +/- 121%, P < 0.01 and 181.4 +/- 56.5%, P < 0.001 respectively). 4. The NK1 receptor selective agonist, [Sar9]SP sulphone (10 nM) evoked a maximal facilitatory action on cholinergic responses of 334.9 +/- 63% (P < 0.01) (pD2 = 8.5 +/- 0.06) an effect which was blocked by the selective NK1-receptor antagonist, CP 96,345 (100 nM) (P < 0.05) but not by the NK2 receptor antagonist, MEN 10,376 (100 nM). The NK2 receptor selective agonist, [beta Ala8]NKA(4-10) (10 nM), produced a maximum enhancement of 278 +/- 83.5% (P < 0.01) (pD2 = 8.7 +/- 0.1) an effect which was blocked by MEN 10,376 (100 nM) (P < 0.05) and not by CP 96,345. [MePhe7]NKB, an NK3 receptor selective agonist was without effect. 5. The rank order of potency of NK2 receptor antagonists against enhancement of cholinergic responses by [Beta Ala8]NKA(4-10) was MEN 10,376> L 659,877> R 396. This pattern together with the observation of the full agonist activity of MDL 28,564 indicates that the NK2 receptors in the rabbit bronchus are similar to those which are present in the rabbit pulmonary artery.6. Neither [Sar9]SP sulphone (5 nM) nor [Beta Ala8]NKA(4- 10) (1 nM) had any effect on contractile responses to ACh (10 MicroM) suggesting a pre-junctional mechanism of action.7. By contrast, in guinea-pig bronchi only the NK1-receptor agonist [Sar9]SP sulphone (3 nM) was effective in enhancing cholinergic neurotransmission but the effect was relatively small (maximal enhancement 25.7 +/- 5.5%, P<0.01). In human bronchial rings all the selective neurokinin agonists were without effect on cholinergic neurotransmission.8. These results suggest that tachykinins may play an important role in modulating cholinergic neurotransmission in rabbit (via NK1 and NK2 receptors) and guinea-pig airways (via NK1 receptor) but have no demonstrable effect on human airways
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PMID:Facilitatory effects of selective agonists for tachykinin receptors on cholinergic neurotransmission: evidence for species differences. 751 99

[3H]Senktide, a highly selective tachykinin NK3 receptor agonist, was used to study tachykinin NK3 receptors of rat and guinea pig brain. Guinea pig brain membranes had a Kd of 3.9 +/- 0.5 nM and a Bmax of 42 fmol/mg. Dose-displacement experiments with neurokinins and selective tachykinin receptor agonists revealed the following order of potency: [MePhe7]neurokinin B > neurokinin B > substance P > neurokinin A. This order is typical for a tachykinin NK3 receptor. To further characterize the specificity of this receptor, the effects of unrelated compounds such as: bradykinin, angiotensin II, bombesin and their structural analogs were also evaluated on the binding of [3H]senktide. Unexpectedly, the angiotensin AT1 receptor antagonists, DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)bip hen yl-4-yl)methyl]imidazole potassium salt), L-158,809 (5,7-dimethyl-2-ethyl-3-[(2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl) methyl]-3H-imidazo[4,5-beta]pyridine H2O) and EXP 3174 (2-n-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]i midazole- 5-carboxylic acid), inhibited the binding of [3H]senktide to its receptor in the guinea pig brain membranes with IC50 values of 18 microM, 25 microM and 50 microM, respectively. Similar effects were also observed with rat brain membranes. Angiotensin II, saralasin ([Sar1,Val5,Ala8]angiotensin II, a peptide angiotensin AT1 receptor antagonist) and PD 123,319 (1-[4-(dimethylamino)3-methylphenyl]methyl-5-(diphenylacetyl)-4,5, 6,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid, a known non-peptide angiotensin AT2 receptor antagonist) did not inhibit the binding of [3H]senktide to either type of membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Non-peptide angiotensin receptor antagonists bind to tachykinin NK3 receptors of rat and guinea pig brain. 751 91

We have studied the structure-activity relationship of a series of tachykinin receptor antagonists based on spantide II. Fifteen novel peptides were tested for their ability to antagonize the electrically evoked tachykinin receptor-mediated response in the isolated rabbit iris sphincter muscle. Substitution or deletion of one to three amino acids in the spantide II sequence caused significant changes in biological activity. Eight of the novel analogues were found to be as potent as or more potent than spantide II and some were found to have better water solubility. We tested the selectivity for different tachykinin receptors of spantide II and two of the eight most potent analogues. They all interacted with tachykinin NK1 (rabbit jugular vein) and tachykinin NK2 (rabbit pulmonary artery) receptors with pA2 values of about 6.5-7.5 at the NK1 receptor and of 5.9-7.2 at the NK2 receptor, while being inactive at the tachykinin NK3 receptor (rat portal vein). Spantide II and the novel analogues were without effect on electrically evoked cholinergic responses of the isolated rabbit iris sphincter and on electrically evoked sympathetic responses of the guinea-pig vas deferens; moreover, they were without local anaesthetic-like effects on action potentials of the frog sciatic nerve, which suggests that they do not produce a general neurosuppressive effect. They were as effective as or slightly less effective than spantide II in causing histamine release from rat peritoneal mast cells.
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PMID:Pharmacological assessment of spantide II analogues. 752 43

The present study investigated the effect of 24-h continuous ICV infusion of four different tachykinins on the enhanced need-free sodium intake induced by previous repeated sodium depletions in female rats. Female rats were employed because, in response to sodium depletions, they develop a higher need-free sodium intake than male rats. The following tachykinins were used: eledoisin, substance P (SP), [Sar9,Met(O2)11]SP and [Asp5,6,MePhe8]SP(5-11), also referred to as NH2-senktide, all at the same doses of 300 or 600 ng/h x 24 h. Food pellets, water, and 3% NaCl sodium solution were freely available. Eledoisin and NH2-senktide were more potent than SP in reducing the need-free sodium intake. On the other hand, [Sar9,Met(O2)11]SP had no effect. None of the tachykinins employed completely blocked the intake. Water intake was reduced, but this reduction was apparently a consequence of reduced intake of hypertonic sodium chloride solution, because at the same doses TKs did not inhibit water intake in a single-bottle test. Food intake remained unchanged at either dose used. These findings confirm previous studies in which pulse injection of the same drugs potently inhibited sodium intake. They also demonstrate that tachykinins endowed with high affinity for the NK3 receptor are the most potent in inhibiting sodium intake. Furthermore, these findings indicate that the tachykinins reduce the need-free sodium intake only during the infusion period, indicating that in these conditions they do not evoke either aversion for salt, or toxic consequences in the follow-up period.
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PMID:Effect of tachykinins on the need-free sodium intake of female rats: a continuous intracerebroventricular infusion study. 752 26

Human tachykinin NK3 receptors expressed in Chinese hamster ovary (CHO-K1) cells were characterised using the novel radioligand [125I]iodohistidyl,[MePhe7]neurokinin B ([125I][MePhe7]neurokinin B). [125I][MePhe7]neurokinin B was shown to label human NK3 binding sites with high affinity in a saturable and reversible manner. The rank order of affinity of a range of tachykinin ligands confirmed that the tachykinin receptor expressed was the NK3 receptor type. An interspecies comparison of NK3 binding sites revealed pharmacological differences between human, guinea pig and rat tachykinin NK3 receptors. The NK2 selective antagonist SR 48968, inhibited binding of [125I][MePhe7]neurokinin B to NK3 binding sites with Ki values of 287 nM and 205 nM in human and guinea pig respectively, but was > 30-fold less active in the rat.
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PMID:Characterisation of [125I][MePhe7]neurokinin B binding to tachykinin NK3 receptors: evidence for interspecies variance. 753 Feb 7


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