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)

NMDA receptors are composed of proteins from two families: NMDAR1 and NMDAR2. We used quantitative double-label in situ hybridization to examine in rat brain the expression of NMDAR1, NMDAR2A, NMDAR2B, and NMDAR2C mRNA in six neurochemically defined populations of striatal neurons: preproenkephalin (ENK) and preprotachykinin (SP) expressing projection neurons, and somatostatin (SOM), glutamic acid decarboxylase 67 (GAD67), parvalbumin (PARV), and choline acetyltransferase (ChAT) expressing interneurons. NMDAR1 was expressed by all striatal neurons: strongly in ENK, SP, PARV and ChAT neurons, and less intensely in SOM and GAD67 positive cells. NMDAR2A mRNA was present at moderate levels in all striatal neurons except those containing ChAT. Labeling for NMDAR2B was strong in projection neurons and ChAT interneurons, and only moderate in SOM, GAD67 and PARV interneurons. NMDAR2C was scarce in striatal neurons, but a low level signal was detected in GAD67 positive cells. NMDAR2C expression was also observed in small cells not labeled by any of the markers, most likely glia. These data suggest that all striatal neurons have NMDA receptors, but different populations have different subunit compositions which may affect function as well as selective vulnerability.
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PMID:Expression of NMDA glutamate receptor subunit mRNAs in neurochemically identified projection and interneurons in the striatum of the rat. 988

N-methyl-D-aspartate (NMDA) receptors are composed of subunits from two families: NR1 and NR2. We used a dual-label in situ hybridization technique to assess the levels of NR1 and NR2A-D messenger ribonucleic acid (mRNA) expressed in projection neurons and interneurons of the human striatum. The neuronal populations were identified with digoxigenin-tagged complementary RNA probes for preproenkephalin (ENK) and substance P (SP) targeted to striatal projection neurons, and somatostatin (SOM), glutamic acid decarboxylase 67 kD (GAD(67)), and choline acetyltransferase (ChAT) targeted to striatal interneurons. Intense NR1 signals were found over all striatal neurons. NR2A signals were high over GAD(67)-positive neurons and intermediate over SP-positive neurons. ENK-positive neurons displayed low NR2A signals, whereas ChAT- and SOM-positive neurons were unlabeled. NR2B signals were intense over all neuronal populations in striatum. Signals for NR2C and NR2D were weak. Only ChAT-positive neurons displayed moderate signals, whereas all other interneurons and projection neurons were unlabeled. Moderate amounts of NR2D signal were detected over SOM- and ChAT-positive neurons; GAD(67)- and SP-positive striatal neurons displayed low and ENK-positive neurons displayed no NR2D hybridization signal. These data suggest that all human striatal neurons have NMDA receptors, but different populations have different subunit compositions that may affect function as well as selective vulnerability.
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PMID:Expression of NMDA receptor subunit mRNAs in neurochemically identified projection and interneurons in the human striatum. 1074 12

Alpha-actinin (alpha-actinin-2) is a protein which links the NR1 and NR2B subunits of N-methyl-D-aspartate (NMDA) glutamate receptors to the actin cytoskeleton. Because of the importance of NMDA receptors in modulating the function of the striatum, we have examined the localization of alpha-actinin-2 protein and mRNA in striatal neurons, and its biochemical interaction with NMDA receptor subunits present in the rat striatum. Using an alpha-actinin-2-specific antibody, we found intense immunoreactivity in the striatal neuropil and within striatal neurons that also expressed parvalbumin, calretinin and calbindin. Conversely, alpha-actinin-2 immunoreactivity was not detected in neurons expressing choline acetyltransferase and neuronal nitric oxide synthase. Dual-label in situ hybridization revealed that the highest expression of alpha-actinin-2 mRNA is in substance P-containing striatal projection neurons. The alpha-actinin-2 mRNA is also present in enkephalinergic projection neurons and interneurons expressing parvalbumin, choline acetyl transferase and the 67-kDa isoform of glutamic acid decarboxylase, but was not detected in somatostatin-expressing interneurons. Immunoprecipitation of membrane protein extracts showed that alpha-actinin-2 is present in heteromeric complexes of NMDA subunits, but is not associated with AMPA receptors in the striatum. A subunit-specific anti-NR1 antibody co-precipitated major fractions of NR2A and NR2B subunits, but only a minor fraction of striatal alpha-actinin-2. Conversely, alpha-actinin-2 antibody immunoprecipitated only modest fractions of striatal NR1, NR2A and NR2B subunits. These data demonstrate that alpha-actinin-2 is a very abundant striatal protein, but exhibits cellular specificity in its expression, with very high levels in substance-P-containing projection neurons, and very low levels in somatostatin and neuronal nitric oxide synthase interneurons. Despite the high expression of this protein in the striatum, only a minority of NMDA receptors are linked to alpha-actinin-2. This interaction may identify a subset of receptors with distinct anatomical and functional properties.
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PMID:alpha-actinin-2 in rat striatum: localization and interaction with NMDA glutamate receptor subunits. 1092 45

Studies have implicated substance P (SP) in the regulation of affective behaviour, memory function, pain influx, stress and opioid reward. All these dimensions are known to involve glutamate transmission mediated through the N-methyl-D-aspartate (NMDA) receptor. The SP N-terminal fragment SP(1-7) is shown to share some but oppose other effects of the parent compound. We have examined the effect of intracerebroventricular injections of SP(1-7) on the expression of the NMDA receptor subunits NR1, NR2A and NR2B mRNAs in the spinal cord and in discrete areas of the male rat brain. The results indicated that the heptapeptide induced a dose-dependent upregulation of the NR2A transcript in hippocampus, periaqueductal grey and ventral tegmental area, already within a few hours. The level of the NR2B mRNA was increased in hippocampus and nucleus accumbens. The expression of the transcript of the NR1 was enhanced in hippocampus and nucleus accumbens but attenuated in spinal cord. The observed effects of the SP(1-7) fragment are in agreement with what could be expected from the known effects of the heptapeptide on various behaviours involving glutamate transmission.
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PMID:Intracerebroventricular injection of the N-terminal substance P fragment SP(1-7) regulates the expression of the N-methyl-D-aspartate receptor NR1, NR2A and NR2B subunit mRNAs in the rat brain. 1097 86

The present study examined the levels of NMDA receptor NR2 subunit tyrosine phosphorylation in a rat model of inflammation and correlated it with the development of inflammation and hyperalgesia. Hindpaw inflammation and hyperalgesia were induced by intraplantar injection of complete Freund's adjuvant. Proteins from the spinal cord (L4-L5) were immunoprecipitated with anti-NR2A or anti-NR2B antibodies and used for subsequent analysis using 4G-10, a specific anti-phosphotyrosine antibody. Compared with naive rats, there was a rapid and prolonged increase in tyrosine phosphorylation of the NR2B, but not NR2A, subunit after inflammation. The increase in NR2B tyrosine phosphorylation was dependent on primary afferent drive because (1) the phosphorylation correlated with the temporal profile of inflammation and hyperalgesia, (2) shorter-duration noxious stimulation produced a rapid and shorter-lasting increase in phosphorylation, and (3) local anesthetic block of the injected paw reversibly blocked inflammation-induced NR2B tyrosine phosphorylation and delayed hyperalgesia. The increase in NR2B tyrosine phosphorylation was abolished by intrathecal pretreatment with genistein, a tyrosine kinase inhibitor; PP2, an Src family tyrosine kinase inhibitor; AIDA, a group I metabotropic glutamate receptor antagonist; L733,060, an NK1 tachykinin receptor antagonist, and chelerythrine, a protein kinase C inhibitor. In addition, intrathecal PP2 delayed the onset of mechanical hyperalgesia and allodynia. These findings correlate in vivo NMDA receptor tyrosine phosphorylation with the development and maintenance of inflammatory hyperalgesia and suggest that signal transduction upstream to NR2B tyrosine phosphorylation involves G-protein-coupled receptors and PKC and Src family protein tyrosine kinases.
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PMID:Tyrosine phosphorylation of the NR2B subunit of the NMDA receptor in the spinal cord during the development and maintenance of inflammatory hyperalgesia. 1212 79

Intrathecal (i.t.) administration of big dynorphin (1-10 fmol), a prodynorphin-derived peptide consisting of dynorphin A and dynorphin B, to mice produced a characteristic behavioral response, the biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 5-15 min after an injection. Dynorphin A produced a similar response, though the doses required were higher (0.1-30 pmol) whereas dynorphin B was practically inactive even at 1000 pmol. The behavior induced by big dynorphin (3 fmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.125-2 mg/kg) and also dose-dependently, by i.t. co-administration of D(-)-2-amino-5-phosphonovaleric acid (D-APV) (1-4 nmol), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (0.25-4 nmol), an NMDA ion-channel blocker, and ifenprodil (2-8 pmol), an inhibitor of the NMDA receptor ion-channel complex interacting with the NR2B subunit and the polyamine recognition site. On the other hand, naloxone, an opioid receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [D-Phe(7),D-His(9)]-substance P(6-11), a specific antagonist for substance P (NK1) receptors, and MEN-10376, a tachykinin NK2 receptor antagonist, had no effect. These results suggest that big dynorphin-induced nociceptive behavior is mediated through the activation of the NMDA receptor ion-channel complex by acting on the NR2B subunit and/or the polyamine recognition site but not on the glycine recognition site, and does not involve opioid, non-NMDA glutamate receptor mechanisms or tachykinin receptors in the mouse spinal cord.
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PMID:Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-D-aspartate receptor mechanism. 1236 99

Functional dyspepsia is a clinical syndrome defined by chronic or recurrent pain or discomfort in the upper abdomen of unknown origin. Although generally accepted, investigators differently interpret this definition and clinical trials are often biased by inhomogeneous inclusion criteria. The poorly defined multifactorial pathogenesis of dyspeptic symptoms has hampered efforts to develop effective treatments. A general agreement exists on the irrelevant role played by Helicobacter pylori in the pathophysiology of functional dyspepsia. Gastric acid secretion is within normal limits in patients with functional dyspepsia but acid related symptoms may arise in a subgroup of them. Proton pump inhibitors appear to be effective in this subset of patients with dyspepsia. Non-painful dyspeptic symptoms are suggestive of underlying gastrointestinal motor disorders and such abnormalities can be demonstrated in a substantial proportion of patients. Postprandial fullness and vomiting have been associated with delayed gastric emptying of solids, and early satiety and weight loss to postcibal impaired accommodation of the gastric fundus. Prokinetics have been shown to exert beneficial effects, at least in some patients with dyspepsia. In contrast, drugs enhancing gastric fundus relaxation have been reported to improve symptoms, although conflicting results have also been published. An overdistended antrum may also generate symptoms, but its potential pathogenetic role and the effects of drugs on this abnormality have never been investigated formally. Visceral hypersensitivity plays a role in some dyspeptic patients and this abnormality is also a potential target for treatment. Both chemo- and mechanoreceptors can trigger hyperalgesic responses. Psychosocial abnormalities have been consistently found in functional digestive syndromes, including dyspepsia. Although useful in patients with irritable bowel syndromes (IBS), antidepressants have been only marginally explored in functional dyspepsia. Among the new potentially useful agents for the treatment of functional dyspepsia, serotonin 5-HT(4) receptor agonists have been shown to exert a prokinetic effect. Unlike motilides, 5-HT(4) receptor agonists do not appear to increase the gastric fundus tone and this may contribute to improve symptoms. 5-HT(3) receptor antagonists have been investigated mainly in the IBS and the few studies performed in functional dyspepsia have provided conflicting results. Also, kappa-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but available results in functional dyspepsia are scanty and inconclusive. Other receptors that represent potential clinical targets for antagonists include purinoceptors (i. e., P2X2/3 receptors), NMDA receptors (NR2B subtype), protease-activated receptor-2, the vanilloid receptor-1, tachykinin receptors (NK(1)/NK(2)) and cholecystokinin (CCK)(1) receptors.
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PMID:New developments in the treatment of functional dyspepsia. 1267 73

Dopamine (DA) and glutamate neurotransmission is thought to be critical for psychostimulant drugs to induce immediate early genes (IEGs) in the caudate-putamen (CPu). We report here, however, that the ability of DA and glutamate NMDA receptor antagonists to attenuate amphetamine-evoked c-fos mRNA expression in the CPu depends on environmental context. When given in the home cage, amphetamine induced c-fos mRNA expression predominately in preprodynorphin and preprotachykinin mRNA-containing neurons (Dyn-SP+ cells) in the CPu. In this condition, all of the D1R, D2R and NMDAR antagonists tested dose-dependently decreased c-fos expression in Dyn-SP+ cells. When given in a novel environment, amphetamine induced c-fos mRNA in both Dyn-SP+ and preproenkephalin mRNA-containing neurons (Enk+ cells). In this condition, D1R and non-selective NMDAR antagonists dose-dependently decreased c-fos expression in Dyn-SP+ cells, but neither D2R nor NR2B-selective NMDAR antagonists had no effect. Furthermore, amphetamine-evoked c-fos expression in Enk+ cells was most sensitive to DAR and NMDAR antagonism; the lowest dose of every antagonist tested significantly decreased c-fos expression only in these cells. Finally, novelty-stress also induced c-fos expression in both Dyn-SP+ and Enk+ cells, and this was relatively resistant to all but D1R antagonists. We suggest that the mechanism(s) by which amphetamine evokes c-fos expression in the CPu varies depending on the stimulus (amphetamine vs. stress), the striatal cell population engaged (Dyn-SP+ vs. Enk+ cells), and environmental context (home vs. novel cage).
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PMID:Amphetamine-evoked c-fos mRNA expression in the caudate-putamen: the effects of DA and NMDA receptor antagonists vary as a function of neuronal phenotype and environmental context. 1280 22

We have previously shown that spermine, a basic polyamine, and big dynorphin, a basic polypeptide, induce nociceptive behavior if injected intrathecally (i.t.) in mice (see [Pain 86 (2000) 55-61] and [Brain Res. 952 (2002) 7-14]). This suggests that other basic molecules might have the same effects. Here, i.t. administration of poly-L-lysine (12 and 36 pg) to mice was found to produce the same characteristic behavioral response, biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 0-10 min after injection. The behavior induced by poly-L-lysine (12 pg) was dose-dependently inhibited by intraperitoneal injection of morphine (0.25-4 mg/kg) and also dose-dependently, by i.t. co-administration of D-(-)-2-amino-5-phosphonovaleric acid (D-APV) (1-4 nmol), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine hydrogen maleate (MK-801) (0.0156-4 nmol), an NMDA ion-channel blocker, and ifenprodil (2-8 nmol), an antagonist of the polyamine recognition site and the NR2B-containing NMDA receptor subtype. On the other hand, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [D-Phe7, d-His9]-substance P (6-11), a specific antagonist for substance P (NK1) receptors, or MEN-10,376, a tachykinin NK2 receptor antagonist, had no effect. These results confirm the observations obtained with other basic molecules and suggest that the behavior induced by poly-l-lysine is mediated through the activation of the NMDA receptor ion-channel complex acting either on the polyamine recognition site or on the NR2B subunit.
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PMID:Nociceptive behavior induced by poly-L-lysine and other basic compounds involves the spinal NMDA receptors. 1508 81

This study assessed the involvement of NMDA and group I metabotropic glutamate receptors, and tachykinin NK1 and NK3 receptors, in central sensitization of withdrawal reflexes in the decerebrated rabbit. Reflexes evoked in the ankle flexor tibialis anterior and the knee flexor semitendinosus by electrical stimulation at the base of the toes were enhanced for 29-63 min after application of 20% mustard oil to the tips of the toes. Selective antagonists of mGlu1, mGlu5, NMDA and NR2B-subunit-containing NMDA glutamate receptors, as well as NK1, and NK3 receptors, and a non-selective blocker of all tachykinin receptors, were assessed for their effects on the magnitude and duration of the increase in reflexes induced by mustard oil. Dizocilpine, an antagonist of all NMDA receptors (1 mg intrathecal) abolished facilitation of tibialis anterior reflexes and significantly reduced the magnitude and duration of increase of the semitendinosus response. The NR2B-subtype selective antagonist CP-101,606 decreased the magnitude of facilitation of both reflexes but had no effect on duration of enhancement. Selective antagonists for the mGlu1 (CPCCOEt, 1-3 mg intrathecal), mGlu5 (MPEP, 0.2-1 mg intrathecal), NK1 (L-733,060, 0.3 mg intrathecal) or NK3 (SR 142,801, 1 mg kg(-1) i.v.) receptors had no effect on the amplitude or duration of sensitization. However, the non-selective tachykinin receptor blocker ZD-6021 (0.3 mg intrathecal) reduced the amplitude but not the duration of sensitization in the flexor reflexes. Combination of ZD-6021 with CP-101,606 (doses as above) decreased both aspects of the sensitization response. Dizocilpine reduced reflexes evoked from the heel per se, and dizocilpine, CP-101,606 and ZD-6021 reduced arterial blood pressure. Otherwise the drugs used had no effects on baseline variables. The present data confirm the importance of NMDA receptors as a critical part of the process of central sensitization, provide no evidence for a role of metabotropic glutamate receptors, and show that simultaneous blockade of all tachykinin receptors is required to reveal their role in hyperalgesia. The data further indicate that a combined pharmacological approach offers a potential way forward for the development of new antihyperalgesic agents.
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PMID:Glutamate and tachykinin receptors in central sensitization of withdrawal reflexes in the decerebrated rabbit. 1512 48


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