Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: CAS:6893-26-1 (glutamate)
73,096 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the guinea pig hippocampus, kappa 1-opioid binding sites were primarily localized in the molecular layer of the dentate gyrus as shown by autoradiography using either the kappa 1-selective radioligand 3H-U69,593 or the nonselective radioligand 3H-diprenorphine in the presence of unlabeled mu- and delta-blocking ligands. In this region, the electrophysiological effects of kappa 1-receptor activation were identified using extracellular and intracellular recordings of dentate granule cell responses. The amplitude of the extracellularly recorded population spike was reduced by U69,593 with an EC50 of 26 nM; this effect was reversible and blocked by the opioid antagonist naloxone. The kappa 1-selective antagonist norbinaltorphimine also blocked the effect of U69,593 with an apparent equilibrium dissociation constant (Ki) of 0.26 nM determined by Schild analysis in the physiologic assay. This value agreed well with the Ki for norbinaltorphimine at kappa 1-binding sites measured by radioligand binding displacement (0.24 nM). These results indicate that the electrophysiologic response observed was likely mediated by kappa 1-receptors. As seen with U69,593, dynorphin B, an endogenous opioid peptide that is present in the dentate gyrus, also inhibited the population spike response. mu- and delta-selective opioid agonists had no effect on the amplitude of the maximally evoked response. Intracellular recordings of dentate granule cells showed no direct effects of U69,593 on the granule cells themselves. However, analysis of synaptic potentials revealed that U69,593 significantly reduced the amplitude of glutaminergic EPSPs evoked by afferent stimulation without affecting IPSP amplitudes. The specific effect of U69,593 application on granule cell EPSPs indicates that presynaptic kappa 1-receptor activation inhibits glutamate release from perforant path terminals in the molecular layer of the dentate gyrus. These results suggest that endogenous dynorphins present in the granule cells may act as feedback inhibitors of the major excitatory input to the dentate gyrus.
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PMID:Kappa-opioids decrease excitatory transmission in the dentate gyrus of the guinea pig hippocampus. 134 43

Administration of dynorphin A-(1-17) (Dyn 1-17), through a microdialysis probe stereotaxically placed into rat hippocampus, caused marked increases in the extracellular levels of glutamate and aspartate. The degree and duration of elevation of these excitatory amino acids (EAA) induced by Dyn 1-17 were dose dependent but were not modified by the centrally active opioid receptor antagonist nalmefene. At comparable doses, Dyn 2-17, which is inactive at the opioid receptor, produced similar alterations in EAA as Dyn 1-17, whereas Dyn 1-8 caused significantly smaller changes of glutamate. Dynorphin and EAAs have each been implicated as pathophysiological factors in brain or spinal cord injuries, with dynorphin's actions shown to involve both opioid and non-opioid components. The present observations indicate a direct potential linkage between dynorphin and excitotoxin mechanisms of CNS injury and provide further support for the concept that dynorphin's pathophysiologic effects may include non-opioid actions of this peptide.
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PMID:Dynorphin increases extracellular levels of excitatory amino acids in the brain through a non-opioid mechanism. 134 3

Selective antagonists of N-methyl-D-aspartate (NMDA) excitatory amino acid (EAA) receptors have been shown to protect against dynorphin-A (DYN)-induced paralysis and neurotoxicity in the spinal cord. To test the hypothesis that either DYN-induced paralysis or neurotoxicity involves an enhanced release of EAAs, we used microdialysis to monitor aspartate (Asp) and glutamate (Glu) release in both the lumbar spinal cord extracellular fluid (ECF) and the spinal cord cerebral spinal fluid (CSF) of conscious rats in response to DYN (1-13). Injection of 5 nmol of DYN produced temporary paralysis in 8 of 10 animals, but did not significantly change Asp or Glu release in either the ECF or the CSF. Injection of 20 nmol of DYN caused permanent paralysis and neuronal cell loss in all animals tested as well as a significant increase of Asp and Glu in both the ECF and the CSF, and a decrease in glutamine (Gln) release only in the ECF. Pretreatment with 1 mg/kg of the NMDA antagonist MK-801 blocked both paralysis and amino acid changes in the ECF. Pretreatment of animals with 5 mg/kg naloxone inhibited glutamate release in the ECF, but did not block paralysis, Asp release or inhibition of Gln release. As MK-801 sensitive paralysis by DYN was not mediated through enhanced EAA release, we examined whether DYN could act through postsynaptic facilitation of NMDA receptors by testing the ability of DYN to alter the magnitude of a behavioral response produced by intrathecal injection of NMDA in mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective potentiation of NMDA-induced activity and release of excitatory amino acids by dynorphin: possible roles in paralysis and neurotoxicity. 134 53

The effects of dynorphin A(1-8) (DA1-8) microinjected into various areas of the hippocampal formation (HF) on the mean blood pressure (MBP) and heart rate (HR) were investigated in the alpha-chloralose-anesthetized rat. Intra-HF injection of DA1-8 dose-dependently (0.5-50 nmol) reduced MBP and HR. Depressor and bradycardic responses also occurred following microinjection of the excitatory amino acid l-glutamate (1 M, 0.2-0.4 microliter) into the DA1-8-sensitive sites. By contrast, administration of 4% lidocaine (0.2-0.4 microliter) into the same HF sites failed to affect MBP and HR. Pretreatment of the HF with the kappa opioid receptor antagonist nor-binaltorphimine at a dose of 2 to 4 nmol, which itself had no significant influence on basal MBP and HR, almost totally abolished the depressor and bradycardic responses induced by HF injection of DA1-8. DA1-8 at a dose of 10 nmol produced no significant alterations in the frequency of respiration and blood PaO2 and PaCO2 and artificial ventilation did not change the cardiovascular responses of DA1-8. Atropine given i.v. almost totally eliminated the bradycardia and partially prevented the hypotensive responses to intra-HF DA1-8. The data indicate that exogenous administration of DA1-8 into the HF is capable of producing substantial inhibition of peripheral cardiovascular function. Because lidocaine was without effect, the hypotension and bradycardia most likely resulted from an augmentation of an excitatory process rather than from direct inhibition of hippocampal neurons around the injection sites. The effects appear to involve activation of kappa opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Centrally mediated cardiovascular actions of dynorphin A(1-8) on rat hippocampal formation. 134 45

This experiment examined the effects of intracerebroventricularly (i.c.v.) administered kainic acid (KA) on the subsequent ex vivo release of L-glutamate (Glu) and dynorphin B-like immunoreactivity (Dyn B-LI) from isolated rat hippocampal mossy fiber (MF) synaptosomes at 4.5 h, 20 h or 48 h after administration of 0.5 microgram/microliter KA. The Dyn B-LI content in the synaptosomal fraction initially decreased at 4.5 h and then rebounded and remained elevated above control levels at 20 h and 48 h. The K(+)-evoked release of Dyn B-LI from the synaptosomes was markedly depressed at 4.5 h after KA and remained significantly below control levels at 20 h and 48 h. In contrast, KA caused no change in the K(+)-evoked release of Glu at 4.5 h as compared to control levels, but did result in a significant decrease in Glu release at 20 h and 48 h. These data indicate a persistent effect of i.c.v. KA on neurotransmission at MF-CA3 synapses in rat hippocampus, resulting in a suppression of the release of Glu as well as the opioid peptide, Dyn B.
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PMID:Kainic acid depresses the ex vivo release of dynorphin B and glutamate from rat hippocampal mossy fiber synaptosomes. 135 75

Topical methionine enkephalin, leucine enkephalin, and dynorphin (10(-6)M) previously have been observed to produce prominent pial arteriolar dilation. Dilation to these opioids could be caused directly by opioids acting on vascular receptors, or indirectly, as a consequence of increased metabolism. Therefore, we examined this possibility by determining the influence of opioids on cerebral glucose utilization in piglets with closed cranial windows using the [14C]deoxyglucose method. Qualitatively, the autoradiographic images expressed as a change in relative optical density from vehicle were unchanged by these opioids. Quantitatively, the opioids similarly had no effect on cerebral glucose utilization (53 +/- 5, 70 +/- 8, 63 +/- 5, and 52 +/- 3, mumol.100 g-1.min-1 for vehicle, methionine enkephalin, leucine enkephalin, and dynorphin, respectively). In contrast, topical glutamate (10(-3) M) produced similar dilation but increased cerebral glucose utilization (41 +/- 3 vs 89 +/- 8 mumol.100 g-1.min-1 for vehicle and glutamate, respectively). Therefore, these opioids do not appear to produce vascular effects through a change in cerebral metabolic utilization of glucose.
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PMID:The influence of opioids on local cerebral glucose utilization in the newborn pig. 135 77

Opioid agonists specific for the mu, delta, and kappa opioid receptor subtypes were tested for their ability to modulate potassium-evoked release of L-glutamate and dynorphin B-like immunoreactivity from guinea pig hippocampal mossy fiber synaptosomes. The kappa opioid agonists U-62,066E and (-) ethylketocyclazocine, but not the mu agonist [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAGO) nor the delta agonist [D-Pen2,5]enkephalin (DPDE), inhibited the potassium-evoked release of L-glutamate and dynorphin B-like immunoreactivity. U-62,066E, but not DAGO or DPDE, also inhibited the potassium-evoked rise in mossy fiber synaptosomal cytosolic Ca2+ levels, indicating a possible mechanism for kappa agonist inhibition of transmitter release. DAGO and DPDE were found to be without any effect on cytosolic Ca2+ levels or transmitter release in this preparation. The U-62,066E inhibition of the potassium-evoked rise in synaptosomal cytosolic Ca2+ levels was partially attenuated by the opioid antagonist quadazocine and insensitive to the delta-opioid specific antagonist ICI 174,864 and the mu opioid-preferring antagonists naloxone and naltrexone. Quadazocine also reversed U-62,066E inhibition of the potassium-evoked release of L-glutamate, but not dynorphin B-like immunoreactivity. These results suggest that kappa opioid agonists inhibit transmitter release from mossy fiber terminals through both kappa opioid and non-kappa opioid receptor mediated mechanisms.
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PMID:Kappa opioid agonists inhibit transmitter release from guinea pig hippocampal mossy fiber synaptosomes. 135 13

In the present studies, an attempt was made to elucidate the role of endogenous opioid inputs to the depressor region of the caudal ventrolateral medulla in the tonic regulation of arterial pressure and to examine the subtype(s) of receptor underlying any observed effects by use of receptor-specific antagonists. The depressor region of the caudal ventrolateral medulla in chloralose-anesthetized, artificially ventilated rabbits was functionally identified by injection of l-glutamate (5 nmol). Bilateral injection of the non-selective opioid antagonist naloxone (0.3, 5 and 20 nmol) into the caudal ventrolateral medulla produced a dose-dependent depressor response, accompanied by a bradycardia, suggesting a tonically active inhibitory opioid input to this region. Bilateral injection of the selective delta-receptor antagonist ICI 174,864 (0.3 nmol) or of the kappa-receptor antagonist nor-binaltorphimine (1 nmol), also markedly reduced both arterial pressure and heart rate. In contrast, injection of the mu-selective antagonist beta-funaltrexamine (0.3-0.6 nmol) produced no effect on arterial pressure or heart rate. These data support the hypothesis that tonically active endogenous opioid inputs, possibly enkephalinergic and/or dynorphinergic, inhibit the depressor neurones of the caudal ventrolateral medulla in the rabbit through activation of delta- and kappa-receptors. Surprisingly, injection of the opioid agonists leu-enkephalin (1 nmol) or dynorphin 1-13 (0.1 nmol), but not the selective mu-receptor agonist DAGO (1 nmol), in the depressor area of the caudal ventrolateral medulla also induced naloxone-sensitive (5 mg/kg, i.v.) decreases in both arterial pressure and heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endogenous opioids tonically inhibit the depressor neurones in the caudal ventrolateral medulla of rabbits: mediation through delta- and kappa-receptors. 164 20

The selective kappa opioid agonist U-50,488H was tested for its ability to modulate the potassium-induced rise of cytosolic Ca2+ in, and transmitter release from, guinea pig hippocampal mossy fiber synaptosomes. U-50,488H dose dependently inhibited the potassium-induced rise in synaptosomal free Ca2+ levels. This inhibition was attenuated by the selective kappa opioid antagonist nor-binaltorphimine, but was insensitive to naloxone and the sigma opioid antagonist ICI 174,864. U-50,488H also dose dependently depressed the potassium-induced release of L-glutamate and dynorphin B-like immunoreactivity from mossy fiber synaptosomes in a nor-binaltorphimine-sensitive manner. This is the first report to confirm the presence of a presynaptic kappa opioid receptor in the hippocampal mossy fiber-CA3 synapse and the nature of its influence on neurotransmitter release. The present results may be used to suggest that endogenous dynorphin peptides interact with this kappa opioid receptor to autoregulate the excitatory mossy fiber synaptic input.
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PMID:U-50,488H inhibits dynorphin and glutamate release from guinea pig hippocampal mossy fiber terminals. 167 97

Excitatory amino acid agonists and antagonists were evaluated for their ability to affect the concomitant release of endogenous L-glutamate and dynorphin A(1-8)-like immunoreactivity from guinea-pig hippocampal mossy fiber synaptosomes. Previous work in this laboratory demonstrated that L(+)2-amino-4-phosphonobutyrate inhibits the potassium-evoked release of these endogenous neurotransmitters from guinea-pig but not rat hippocampal mossy fiber synaptosomes. Therefore, the present study was conducted to evaluate excitatory amino acid agonists as indices to the functional properties of this L(+)2-amino-4-phosphonobutyrate-sensitive glutamatergic autoreceptor on mossy fiber terminals. Low micromolar concentrations of quisqualate, but not kainate, N-methyl-D-aspartate, nor RS-alpha-amino-3-hydroxy-5-methyl-4-isoazole-propionic acid, significantly inhibited the potassium-evoked release of both L-glutamate and dynorphin A(1-8)-like immunoreactivity. Quisqualate-induced inhibition of L-glutamate release from mossy fiber terminals was antagonized by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. In contrast, high concentrations of kainate enhanced the potassium-evoked release of L-glutamate and dynorphin A(1-8)-like immunoreactivity, and this potentiation was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione. Kainate (1 mM) was the only agonist which significantly enhanced the basal release of L-glutamate, whereas the spontaneous efflux of dynorphin A(1-8)-like immunoreactivity was not affected by any of the agonists tested. The results presented in this paper suggest the existence of inhibitory and excitatory presynaptic glutamatergic autoreceptors that act to modulate the release of endogenous L-glutamate- and prodynorphin-derived peptides from guinea-pig hippocampal mossy fiber terminals. These inhibitory and excitatory autoreceptors, which are sensitive to quisqualate/L(+)2-amino-4-phosphonobutyrate or kainate, respectively, may play an important role in regulating synaptic activity at glutamatergic synapses throughout the central nervous system.
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PMID:Presynaptic modulation of glutamate and dynorphin release by excitatory amino acids in the guinea-pig hippocampus. 167 99


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