UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms by which glutamate shapes the activity of striatal medium spiny neurons are of fundamental importance to our understanding of normative and pathological striatal physiology. Non-N-Methyl-D-aspartate (non-NMDA) glutamate receptor expression and function were studied in medium spiny neurons with a combination of single cell RT-PCR, immunocytochemistry and whole-cell voltage-clamp techniques. Reverse transcription polymerase chain reaction analysis found that GluR2 mRNA appeared to be the most abundant and widely distributed AMPA receptor mRNA. GluR1 was also commonly detected. However, GluR3 mRNA was preferentially expressed by neurons coexpressing substance P and enkephalin and GluR4 mRNA was not detected in identified medium spiny neurons. All neuronal classes appeared to express GluR5 or GluR6 and/or GluR7 mRNA in addition to kainate (KA) subunit mRNA. Immunocytochemical studies confirmed the mRNA distributions and also revealed that GluR1 protein was largely restricted to dendritic spines. Although the mRNA and protein for both alpha-amino-3-hydroxy-5-methyl-ioxyzole-4-proprionic acid (AMPA) and KA class subunits was detected, the physiological response to glutamatergic ligands and the benzothiadizine cyclothiazide was characteristic of AMPA, not KA receptors. The AMPA receptor antagonist GYKI 52466 blocked the response to AMPA and all but a small transient component of the response to KA. The current-voltage relationship of the AMPA-evoked currents was relatively linear but Ca2+ fluorometry revealed that substantial changes in intracellular Ca2+ concentration accompanied exposure to either agonist. These results argue that somatodendritic non-NMDA glutamate receptors in medium spiny neurons are primarily GluR2-containing receptors of the AMPA class but that activation of these receptors as a group nevertheless results in a significant Ca2+ influx.
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PMID:Physiological and molecular properties of AMPA/Kainate receptors expressed by striatal medium spiny neurons. 969 Nov 98

The use-dependent increase in synaptic strength between primary afferent C-fibres and second-order neurons in superficial spinal dorsal horn may be an important cellular mechanism underlying central hyperalgesia. This long-term potentiation can be blocked by antagonists of the N-methyl-D-aspartate subtype of glutamate receptor, the neurokinin 1 or the neurokinin 2 receptor. We have tested here whether activation of these receptors by superfusion of the spinal cord with corresponding agonists in the absence of presynaptic activity is sufficient to induce long-term potentiation. In urethane anaesthetized rats C-fibre-evoked field potentials were elicited in superficial laminae of lumbar spinal cord by electrical stimulation of the sciatic nerve. In rats with intact spinal cord, controlled superfusion of the spinal cord at recording segments for 60 min with N-methyl-D-aspartate, substance P or neurokinin A never induced long-term potentiation. Spinal superfusion with a mixture of N-methyl-D-aspartate, substance P and neurokinin A also failed to induce long-term potentiation in four rats tested. In spinalized rats, however, long-term potentiation was induced by either N-methyl-D-aspartate (at 10 microM, to 173 +/- 16% of control) substance P (at 10 microM, to 176 +/- 13% of control) or by neurokinin A (at 1 microM, to 198 +/- .20% of control). The induction of long-term potentiation by N-methyl-D-aspartate, substance P or neurokinin A was blocked by intravenous application of the receptor antagonists dizocilpine maleate (0.5 mg/kg), RP67580 (2 mg/kg) or SR48968 (0.2 mg/kg), respectively. Thus, activation of N-methyl-D-aspartate or neurokinin receptors may induce long-lasting plastic changes in synaptic transmission in afferent C-fibres and this effect may be prevented by tonic descending inhibition.
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PMID:Activation of spinal N-methyl-D-aspartate or neurokinin receptors induces long-term potentiation of spinal C-fibre-evoked potentials. 969 27

The modulatory action of substance P on synaptic transmission of CA1 neurons was studied using intra- or extracellular recording from the mouse hippocampal slice preparation. Bath-applied substance P (2-4 microM) or the selective NK1 receptor agonist substance P methylester (SPME, 10 nM-5 microM) depressed field potentials (recorded from stratum pyramidale) evoked by focal stimulation of Schaffer collaterals. This effect was apparently mediated via NK1 receptors since it was completely blocked by the selective NK1 antagonist SR 140333. The field potential depression by SPME was significantly reduced in the presence of bicuculline. Intracellular recording from CA1 pyramidal neurons showed that evoked excitatory postsynaptic potentials (EPSPs) and evoked inhibitory postsynaptic potentials (IPSPs) were similarly depressed by SPME, which at the same time increased the frequency of spontaneous GABAergic events and reduced that of spontaneous glutamatergic events. The effects of SPME on spontaneous and evoked IPSPs were prevented by the ionotropic glutamate receptor blocker kynurenic acid. In tetrodotoxin (TTX) solution, no change in either the frequency of spontaneous GABAergic and glutamatergic events or in the amplitude of responses of pyramidal neurons to 4 microM alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or 10 microM N-methyl-D-aspartate (NMDA) was observed. On the same cells, SPME produced minimal changes in passive membrane properties unable to account for the main effects on synaptic transmission. The present data indicate that SPME exerted its action on CA1 pyramidal neurons via a complex network mechanism, which is hypothesized to involve facilitation of a subset of GABAergic neurons with widely distributed connections to excitatory and inhibitory cells in the CA1 area.
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PMID:Modulation by substance P of synaptic transmission in the mouse hippocampal slice. 978 2

The substantia gelatinosa of the spinal cord (lamina II) is the major site of integration for nociceptive information. Activation of NMDA glutamate receptor, production of nitric oxide (NO), and enhanced release of substance P and calcitonin gene-related peptide (CGRP) from primary afferents are key events in pain perception and central hyperexcitability. By combining reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry for NO-producing neurons with immunogold labeling for substance P, CGRP, and glutamate, we show that (1) NO-producing neurons in lamina IIi are islet cells; (2) these neurons rarely form synapses onto peptide-immunoreactive profiles; and (3) NADPH diaphorase-positive dendrites are often in close spatial relationship with peptide-containing terminals and are observed at the periphery of type II glomeruli showing glutamate-immunoreactive central endings. By means of confocal fluorescent microscopy in acute spinal cord slices loaded with the Ca2+ indicator Indo-1, we also demonstrate that (1) NMDA evokes a substantial [Ca2+]i increase in a subpopulation of neurons in laminae I-II, with morphological features similar to those of islet cells; (2) a different neuronal population in laminae I-IIo, unresponsive to NMDA, displays a significant [Ca2+]i increase after slice perfusion with either substance P and the NO donor 3morpholinosydnonimine (SIN-1); and (3) the responses to both substance P and SIN-1 are either abolished or significantly inhibited by the NK1 receptor antagonist sendide. These results provide compelling evidence that glutamate released at type II glomeruli triggers the production of NO in islet cells within lamina IIi after NMDA receptor activation. The release of substance P from primary afferents triggered by newly synthesized NO may play a crucial role in the cellular mechanism leading to spinal hyperexcitability and increased pain perception.
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PMID:Nitric oxide-producing islet cells modulate the release of sensory neuropeptides in the rat substantia gelatinosa. 985 75

The rostral portion of the nucleus of the solitary tract (NST) contains second-order gustatory neurons, sends projections to the parabrachial complex and brainstem reticular formation, and receives descending projections from several nuclei of the ascending gustatory pathway. Electrophysiological responses of NST neurons can be modulated by several factors, including blood glucose and insulin levels and taste aversion conditioning. We are using extracellular electrophysiological recording in vivo, combined with local microinjection of neurotransmitter agonists and antagonists, to study the mechanisms by which taste responses of cells in the hamster NST can be modulated. Afferent fibers of the chorda tympani (CT) nerve make excitatory synaptic contact with NST neurons; this excitation is probably mediated by the excitatory amino acid glutamate. Microinjection of kynurenic acid, a nonspecific glutamate receptor antagonist, into the NST completely and reversibly blocks afferent input from the CT nerve, produced by either anodal electrical or chemical stimulation of the anterior tongue. The non-NMDA ((RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate) receptor antagonist 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) also completely blocks gustatory input to these cells, whereas the N-methyl-D-aspartate (NMDA) antagonist DL-2-amino-5-phosphonovalerate (APV) produces only a small effect. There are many gamma-aminobutyric acid (GABA)-containing neurons within the NST and taste-responsive NST cells are maintained under a tonic GABAergic inhibition. Microinjection of the GABAA receptor antagonist bicuculline methiodide increases the taste responsiveness of NST neurons, whereas application of GABA inhibits taste responses in these cells. Preliminary data show that GABAergic inhibition can be produced by stimulation of the gustatory cortex. There are both intrinsic substance P (SP)-containing neurons and extrinsic SP-immunoreactive fibers in the rostral NST. Microinjection of SP into the NST enhances the responses of many NST cells to gustatory stimulation; NaCl-best neurons are preferentially excited by SP.
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PMID:Excitatory and inhibitory modulation of taste responses in the hamster brainstem. 992 38

The mechanisms by which dopaminergic and glutamatergic inputs interact to regulate striatal neuropeptide expression during physiological motor activity are poorly understood. In this work, striatal expression of preprotachykinin (PPT) and preproenkephalin (PPE) mRNA was studied by in situ hybridization in rats killed 2 h after treadmill running (36 m/min for 20 min). Treadmill running induced a significant increase in the levels of both PPT (60% increase) and PPE (90% increase) mRNA in the striatum of normal rats. The increase in the level of PPT mRNA was blocked in rats previously subjected to nigrostriatal deafferentation (i.e., 6-hydroxydopamine lesion) or pretreated with D1-receptor antagonist SCH-23390 (0.1 mg/kg), the D2-receptor antagonist eticlopride (0.5 mg/kg), or the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801 (0.1 mg/kg). The running-induced increase in the level of PPE mRNA was blocked in rats pretreated with SCH-23390 or MK-801. Rats subjected to nigrostriatal deafferentation or pretreated with eticlopride showed an increase in PPE mRNA levels (around 150% and 40% increase, respectively), that was enhanced by running (around 230% and 160% increase, respectively). These results suggest that locomotor activity increases, in a NMDA receptor dependent fashion, the excitatory influence of the corticostriatal glutamatergic system on the two populations of striatal projection neurons, as reflected by increases in the levels of PPT and PPE mRNA. The results obtained after dopamine depletion or injection of dopamine receptor antagonists suggest that a concomitant increase in dopamine release may enhance PPT mRNA level in striatonigral neurons via D1 receptors, and reduce PPE mRNA level in striatopallidal neurons via D2 receptors. Additionally, levels of dopamine and glutamate may be regulated by other complex indirect mechanisms.
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PMID:Locomotor-activity-induced changes in striatal levels of preprotachykinin and preproenkephalin mRNA. Regulation by the dopaminergic and glutamatergic systems. 1038 45

In view of the widespread use of non-steroidal anti-inflammatory drugs for treatment of inflammatory pain, we determined the effects of the non-steroidal anti-inflammatory drug, indomethacin, on dorsal horn neurons in the rat spinal cord in vivo. At 2.0-12.0 mg/kg (i.v.), indomethacin depressed the responses of spinal dorsal horn neurons to the effects of iontophoretic application of substance P, N-methyl-D-aspartate, quisqualate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. As indomethacin inhibits cyclo-oxygenase, these are the first data linking prostanoids and possibly arachidonic acid and other eicosanoids to the effects of substance P and glutamate in the spinal dorsal horn. As responses to iontophoretic application can be assumed to have been postsynaptic and as indomethacin had an effect generalized to all excitatory responses, we suggest a postsynaptic site for cyclo-oxygenase. We also suggest that elements in the cyclo-oxygenase signal transduction pathway may thus mediate at least some of the effects of substance P and glutamate receptor activation. Activation of the cyclo-oxygenase pathway in CNS neurons is Ca2- dependent, and activation of both N-methyl-D-aspartate and substance P receptors increases intracellular Ca2+. This led to the expectation that indomethacin would have a greater effect on responses to N-methyl-D-aspartate than to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, but the reverse was observed. Thus, in addition to a mediator role, we hypothesize that an element(s) of the cyclo-oxygenase pathway may regulate the efficacy of excitation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors and perhaps other membrane-bound receptors. The cyclo-oxygenase signal transduction pathway thus appears to play at least two major roles in regulation of sensory processing in the spinal cord. Therefore, non-steroidal anti-inflammatory drugs, via cyclo-oxygenase inhibition, may have multiple actions in control of spinal sensory mechanisms.
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PMID:Mediation and modulation by eicosanoids of responses of spinal dorsal horn neurons to glutamate and substance P receptor agonists: results with indomethacin in the rat in vivo. 1047 75

Substance P and glutamate are present in primary afferent C-fibers and play important roles in persistent inflammatory and neuropathic pain. In the present study, we have examined whether activation of different glutamate receptor subtypes modulates the release of substance P evoked by the C-fiber selective stimulant capsaicin (1 microM) from rat trigeminal nucleus slices. The selective NMDA glutamate receptor agonist L-CCG-IV (1-10 microM) enhanced capsaicin-evoked substance P release about 100%. This facilitatory effect was blocked by 0.3 microM MK-801, a selective NMDA receptor antagonist. The metabotropic glutamate receptor agonists L-AP4 (group III) and DHPG (group I) (30-100 microM) inhibited capsaicin-evoked substance P release by approximately 60%. These inhibitory effects were blocked by the selective metabotropic glutamate receptor antagonist (+/-)-MCPG (5 microM). On the other hand, AMPA and kainate (0.1-10 microM), did not significantly affect capsaicin-evoked substance P release. Thus, substance P release from non-myelinated primary afferents, and possibly nociception, may be under the functional antagonistic control of some metabotropic and ionotropic glutamate receptor subtypes.
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PMID:Opposite modulation of capsaicin-evoked substance P release by glutamate receptors. 1052 15

The expression of 34 transmitter-related genes has been examined in the cholinergic neurones of rat striatal brain slices, with the aim of correlating gene expression with functional activity. The mRNAs encoding types I, II/IIA, and III alpha subunits of the voltage-sensitive sodium channels were detected, suggesting the presence of these three types of sodium channel. Similarly, mRNAs encoding all four alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type glutamate receptor subunits and the NR1 and NR2A, 2B, and 2D subunits of the NMDA-type glutamate receptors were detected, suggesting that various combinations of these subunits mediate the cellular response to synaptically released glutamate. Other mRNAs detected included the NK1 and NK3 tachykinin receptors, all four known adenosine receptors, and the GABA-synthesising enzyme glutamate decarboxylase. Subpopulations of these cholinergic neurones have been identified on the basis of the expression of the NK3 tachykinin receptor in 5% and the trkC neurotrophin receptor in 12% of the cells investigated.
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PMID:Correlating physiology with gene expression in striatal cholinergic neurones. 1064 37

Central release of substance P (SP) in the nucleus tractus solitarius (NTS) may potentiate the reflex responses evoked by baroreceptor afferent input to this medullary nucleus. The mechanism is not known but may involve modulation of responses produced by release of glutamate, the putative primary baroreceptor transmitter, at neurons within the NTS. The principal glutamate receptor subtype proposed to transmit baroreceptor afferent input at second-order neurons is the non-N-methyl-D-aspartate (NMDA) receptor. The present study examined the effects of microinjection of SP into barosensitive regions of the NTS on the depressor and bradycardic response induced by activation of non-NMDA receptors in the NTS by subsequent microinjection of (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), a non-NMDA receptor agonist. Substance P potentiated the non-NMDA receptor-induced depressor response to AMPA in the NTS, evoking a significantly larger change in blood pressure over the same time period. These data suggest that SP may modulate a non-NMDA-miediated component of the baroreflex to influence the control of arterial blood pressure by increasing the sensitivity of the baroreceptor reflex.
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PMID:Potentiation of non-N-methyl-D-aspartate receptor-induced changes in blood pressure by substance P in rats. 1065 18

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