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)

We tested the hypothesis that glutamate, the major excitatory neurotransmitter of the CNS, is also an excitatory neurotransmitter in the enteric nervous system (ENS). Glutamate immunoreactivity was found in cholinergic enteric neurons, many of which were identified as sensory by their co-storage of substance P and/or calbindin. Glutamate immunoreactivity was concentrated in terminal varicosities with a majority of small clear synaptic vesicles. The immunoreactivities of both AMPA and NMDA receptor subunits were also detected on neurons in both submucosal and myenteric plexuses. The immunoreactivity of the EAAC1 neuronal glutamate transporter was widespread in both plexuses. Glutamate evoked depolarizing responses in myenteric neurons that had fast and slow components. The fast component was mimicked by AMPA, and the slow component was mimicked by NMDA. The fast component and the response to AMPA mimicked fast EPSPs evoked in 2/AH neurons; moreover, fast EPSPs as well as fast glutamate and AMPA responses were blocked by selective AMPA antagonists and potentiated by the glutamate uptake inhibitor L-(-)-threo-3-hydroxyaspartic acid. These observations demonstrate, for the first time, the presence of glutamatergic neurons and glutamate-mediated neurotransmission in the ENS.
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PMID:Glutamatergic enteric neurons. 916 36

We have assessed the time course of repeated administration of methamphetamine (METH; 4 mg/kg) and withdrawal on the levels of preprotachykinin (PPT) and preproenkephalin (PPE) mRNA abundance in the caudate-putamen (CPu) and nucleus accumbens (NAc) of the rat brain by in situ hybridization histochemistry. Neostriatal PPT mRNA levels rose gradually between days 1 and 6 of treatment, with the greatest elevation observed at day 6. After 6 days of daily injections twice per day, PPT mRNA increases in dorsomedial (172%) and ventromedial (196%) aspects of the CPu were significantly higher than in dorsolateral (147%) and ventrolateral (135%) subdivisions. Similarly, PPT mRNA levels were increased in the anterior CPu (163%) and NAc (121%). Concurrent administration of METH and the NMDA receptor antagonist MK-801 attenuated METH-induced increases of PPT mRNA in all aspects of the CPu at day 6 of treatment and completely prevented the increase in the NAc. Moreover, animals treated with METH for 6 days and then withdrawn for 15 days displayed PPT mRNA levels in striatum and accumbens that were statistically indistinguishable from those of controls. Adjacent sections from the same brains were used to assess PPE mRNA levels. PPE mRNA levels were transiently elevated in dorsal and ventral aspects of the CPu at day 1 and decayed to control levels at days 3 and 6. The results demonstrate that progressive treatment with methamphetamine causes stepwise elevation of preprotachykinin mRNA levels in the neostriatum. Moreover, the increase of neuropeptide mRNA shows selectivity, since PPE mRNA levels did not display progressive accumulation of message. The effects of progressive METH treatment on neostriatal PPT mRNA expression decay when the drug is withdrawn, suggesting that this neuropeptidergic system may not represent a neuroadaptation sustaining enduring sensitization to amphetamines, but may play a role in the progressive augmentation of locomotor activity elicited by this class of drug.
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PMID:Progressive augmentation of striatal and accumbal preprotachykinin mRNA levels by chronic treatment with methamphetamine and effect of concurrent administration of the N-methyl-D-aspartate receptor antagonist MK-801. 917 11

The spiny and aspiny neuronal populations of the striatum display differential vulnerability to the toxic effects of glutamatergic agonists. Substance P-containing spiny neurons appear to be more vulnerable to NMDA-receptor-mediated toxicity and less susceptible to kainate toxicity than the somatostatin- and neuropeptide Y (NPY)-containing aspiny population. We studied whether selective glutamatergic agonists might have similar differential effects on neuropeptide release from the substance P- and somatostatin/NPY-containing neuronal populations. After collection of a baseline sample, striatal neurons in primary culture were treated with one of the following: phosphate-buffered saline, 56 mM potassium chloride (KCl), 100 microM N-methyl-D-aspartate (NMDA), 100 microM quisqualate, 100 microM kainate, or 100 microM glutamate. Baseline and treatment samples were measured by radioimmunoassay for somatostatin, NPY, and substance P. KCl and kainate provoked a selective release of somatostatin and NPY, whereas substance P measured in the same samples showed no response. By contrast, NMDA elicited a selective release of substance P without a similar increase of either somatostatin or NPY. Quisqualate evoked comparable responses in the three peptides. These results indicate that the glutamatergic regulation of somatostatin and NPY release from aspiny striatal neurons in primary culture is preferentially mediated by the kainate receptor, whereas substance P release is selectively mediated by the NMDA receptor. These findings suggest a preferential expression of functional kainate receptors on the aspiny somatostatin/NPY neurons and of NMDA receptors on the substance-P-containing spiny neurons.
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PMID:Role of glutamate receptor subtypes in the differential release of somatostatin, neuropeptide Y, and substance P in primary serum-free cultures of striatal neurons. 932 51

The N-methyl-D-aspartate (NMDA) receptor is thought to mediate the postsynaptic effects of excitatory amino acids released from primary afferent terminals in the superficial layers of the dorsal horn of the spinal cord where synergistic associations with substance P (SP) have been implicated in the production of hyperalgesia. We examined the electron microscopic dual immunocytochemical localization of SP and the R1 subunit of the NMDA receptor (NMDAR1) in this region to determine the cellular basis for interactions between SP and NMDA receptor ligands. Of 971 profiles immunolabeled for NMDAR1, 40% were dendrites and the remainder were primarily unmyelinated axons and astrocytic processes. In dendrites, NMDAR1-like immunoreactivity (NMDAR1-LI) was associated with synaptic and non-synaptic portions of the plasma membrane, as well as intracellular membranes including smooth endoplasmic reticulum. These NMDAR1-labeled dendrites received synaptic input from unlabeled terminals and from terminals containing SP and/or NMDAR1-LI and they occasionally (25/389) also contained SP. In contrast, of 540 SP-immunoreactive profiles, 60% were axon terminals and the majority (252/324) of these SP-labeled terminals were presynaptic to NMDAR1-containing dendrites. These results provide anatomical evidence that the synergistic nociceptive effects of SP and NMDA ligands are attributed mainly to dual modulation of the activity of single dendritic targets in the dorsal horn of the spinal cord. They also suggest that activation of NMDA receptors may also play a role in the modulation of SP neurons, presynaptic release of SP or other neurotransmitters, and in glial function in the dorsal horn.
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PMID:The N-methyl-D-aspartate (NMDA) receptor is postsynaptic to substance P-containing axon terminals in the rat superficial dorsal horn. 940 57

Sensitization is manifested as an increased response of neurones to a variety of inputs following intense or noxious stimuli. It is one of the simplest forms of learning and synaptic plasticity and it represents an important feature of nociception. In the spinal cord, repeated stimulation (at constant strength) of dorsal root afferents including nociceptive C fibres can elicit a progressive increase in the number of action potentials generated by motoneurones and interneurones. This phenomenon is termed "action potential windup" and is used as a cellular model of pain sensitization developing at the level of the central nervous system. Understanding the mechanisms responsible for windup generation might allow clarification of the cellular mechanisms of pain signalling and development of new strategies for pain treatment. Action potential windup is observed in a minority of cells only, indicating that certain cell-specific mechanisms are responsible for its generation. The most reliable index to predict windup generation is the rate at which the membrane potential is depolarized during repetitive stimulation. This phenomenon has been proposed to be due to gradual recruitment of NMDA receptor activity, to summation of slow excitatory potentials mediated by substance P (and related peptides) or to facilitation of slow calcium channels by metabotropic glutamate receptors. Little is known about the role of synaptic inhibition in windup, although it should not be underestimated. Each theory per se is unable to account for all the experimental observations. Since NMDA receptors are involved in many forms of synaptic plasticity, additional mechanisms such as summation of slow peptidergic potentials, facilitation of slow Ca2+ currents and disinhibition are proposed as necessary to impart specificity to pain-induced sensitization. These additional mechanisms might be species specific and change during development or chronic pain states.
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PMID:Sensitization of pain pathways in the spinal cord: cellular mechanisms. 948 3

The mRNA levels encoding enkephalin and substance P were measured in the rat striatum following cortical ablation, blockade of N-methyl-D-aspartate (NMDA) receptors or inhibition of glutamate release by lamotrigine. Unilateral ablation of the cerebral cortex resulted in a decrease of substance P mRNA levels particularly in the rostral dorsolateral and dorsomedial striatum ipsilateral to the lesion. There was a similar trend for a reduction in levels of enkephalin mRNA. Continuous, intrastriatal infusion of the competitive NMDA receptor antagonist, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, (CPP, 0.12 and 1.2microg/day) decreased both enkephalin mRNA and substance P mRNA in dose-dependent manner evenly throughout the striatum adjacent to the infusion site. Following subchronic administration of the presumed glutamate release inhibitor, lamotrigine (5 and 20mg/kg IP) there was no significant alterations in either enkephalin mRNA or substance P mRNA levels in the striatum. Both enkephalin mRNA and substance P mRNA expression in the rat striatum appear tonically stimulated through postsynaptic NMDA receptor mediated mechanisms. This contrasts with differential dopaminergic modulation of peptides in striatal output neurons.
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PMID:Glutamatergic regulation of striatal peptide gene expression in rats. 962 62

This study used streptozotocin (STZ; 50 mg/kg i.p.) diabetic rats and monitored weekly thermal and mechanical nociceptive thresholds for 8 weeks diabetes. Rats developed mechanical hyperalgesia as soon as 2 weeks after STZ injection. Thermal nociceptive threshold was not altered up to 8 weeks after STZ injection. Four week-diabetic rat mechanical hyperalgesia showed reduced sensitivity to the antinociceptive effect of morphine (5-20 mg/kg i.p.). Furthermore, a reduced sensitivity to the antinociceptive effect of the GABA(B) agonist, (+/-)baclofen, was observed. A dose as high as 16 mg/kg i.p. of (+/-)baclofen was necessary to reverse 4 week-diabetic rat hyperalgesia, whereas in control rats the highest antinociceptive dose devoid of muscle-relaxant effect was 4 mg/kg i.p. The non-peptide antagonist for the substance P, neurokinin, (NK1) receptor, RP 67580 (3-9 mg/kg i.p.) was not effective in reversing the mechanical hyperalgesia associated with 4 week-diabetes. A six day-treatment with an antagonist for the N-methyl-D-aspartate (NMDA) receptor for glutamate, (+)MK-801 (0.1 mg/kg i.p. twice a day), gradually but completely reversed 4 week-diabetes-induced mechanical hyperalgesia. These data suggest that diabetes-induced hyperalgesia may be the consequence of increased activity of primary afferent fibres leading to an increased excitatory tone within the spinal cord. An increased release of glutamate and activation of the NMDA receptor, would maintain the hyperalgesic state. Reduced activity of both opioidergic and GABA(B)ergic inhibitory systems, might exacerbate the increased excitation thus contributing to the ongoing pain. It is suggested that NMDA receptor antagonists may constitute an alternative therapy for diabetic neuropathic pain.
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PMID:A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. 969 68

Normally-innocuous low-intensity tactile stimuli applied to inflamed tissue induce a progressive decrease in the mechanical flexion withdrawal threshold, the phenomenon of progressive tactile hypersensitivity (PTH). The effects of the mu opioid receptor agonist morphine, the non-competitive NMDA receptor antagonist MK801 and the tachykinin NK1 receptor antagonist RP67580 on the development and maintenance of PTH has now been investigated behaviourally in rats inflamed 48 h earlier by intraplantar complete Freund's adjuvant injection. A standard protocol of eight light tactile stimuli applied to the dorsum of the inflamed paw every 4 s at 5 min intervals resulted, over 60 min, in a 70% fall in mechanical threshold from the pre-conditioning baseline value. Morphine administered before the tactile stimuli at 0.05 mg/kg i.p. had no effect on either baseline thresholds or PTH. At 0.5 mg/kg, morphine prevented the establishment of PTH without changing baseline thresholds. At 5 mg/kg morphine produced analgesia, increasing thresholds above the baseline. MK801 pre-treatment at 0.01 and 0.001 mg/kg i.p. significantly attenuated the development of progressive tactile hyperalgesia without an effect on basal thresholds. RP67580 pre-treatment at 0.1 mg/kg i.p. had no effect, but at both I and 10 mg/kg, attenuated progressive tactile hypersensitivity without changing baseline values. To test the effect of the drugs on established PTH, they were administered 90 min after the commencement of intermittent tactile stimulation to the inflamed hindpaw, when thresholds had reached a plateau. Morphine (0.5 mg/kg) and MK801 (0.01 mg/kg) produced only a small reduction in sensitivity and RP67580 (1 mg/kg) had no effect. These results suggest that the induction of inflammatory progressive tactile hypersensitivity is sensitive to morphine, and to a lesser extent NMDA and NKI receptor antagonists, but these compounds at a dose that do not alter baseline values, do not normalise established tactile hypersensitivity.
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PMID:Morphine, the NMDA receptor antagonist MK801 and the tachykinin NK1 receptor antagonist RP67580 attenuate the development of inflammation-induced progressive tactile hypersensitivity. 975 18

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 possible modulation exerted by glutamate on substance P (SP) release from the rat spinal cord has been investigated. The N-methyl-D-aspartate (NMDA) receptor agonist, NMDA (1 microM), increased SP basal outflow by 46.5+/-10.9% (n = 3, P<0.01) without changing the evoked release of the peptide. Conversely, NMDA antagonists but not 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) inhibited both electrically-evoked and capsaicin-induced release of SP. In particular, D-2-amino-5-phosphonopentanoate (D-AP5; 50 microM) inhibited electrically-evoked and capsaicin-induced release of SP by 93+/-2.4% and 93.2+/-3.8% (n = 12, P<0.01), respectively. Functional pharmacological evidence is provided for glutamate exerting a positive feedback on SP release evoked by C fibre stimulation via NMDA receptor activation.
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PMID:NMDA receptor activation modulates evoked release of substance P from rat spinal cord. 988 51


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