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Madden, Ken. "NMDA Receptor Antagonists and Glycine Site NMDA Antagonists." Current Medical Research and Opinion 18, sup2 (January 2002): s27—s31. http://dx.doi.org/10.1185/030079902125000705.
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Pedder, Simon C. J., Robert I. Wilcox, John M. Tuchek, Dennis D. Johnson, and R. D. Crawford. "Attenuation of febrile seizures in epileptic chicks by N-methyl-D-aspartate receptor antagonists." Canadian Journal of Physiology and Pharmacology 68, no. 1 (January 1, 1990): 84–88. http://dx.doi.org/10.1139/y90-012.
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Experimental febrile seizures can be evoked in epileptic chicks by elevation of their body temperature. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists [(3-(±)2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), DL-2-amino-7-phosphosphonoheptanoic acid (APH), DL-2-amino-5-phosphonovaleric acid (APV), D-α-aminoadipic acid (AAA), and DL-α,ε-diaminopimelic acid (DAP)] and the noncompetitive NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801) produced dose-dependent increases in latency to the onset of seizures. Of the drugs tested, MK-801 had the highest potency followed in order by CPP = APH > APV [Formula: see text] AAA > DAP. There was a high correlation (r = 0.995) between the dose capable of doubling seizure latency and the affinity of the competitive NMDA antagonists for the NMDA receptor as determined by in vitro binding assays. These data suggest that NMDA receptor mediated mechanisms may be involved in the production of seizures in response to hyperthermia.Key words: seizures, NMDA antagonists, epileptic chickens, anticonvulsant activity, receptors.
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Heggelund, P., and E. Hartveit. "Neurotransmitter receptors mediating excitatory input to cells in the cat lateral geniculate nucleus. I. Lagged cells." Journal of Neurophysiology 63, no. 6 (June 1, 1990): 1347–60. http://dx.doi.org/10.1152/jn.1990.63.6.1347.
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1. Synaptic mechanisms that might explain the functional properties of the recently discovered class of lagged cells in the dorsal lateral geniculate nucleus (LGN) were analyzed with electrophysiological and pharmacologic techniques. To study the type of excitatory amino acid (EAA) receptor that mediates visual responses of lagged cells, we recorded the response of single cells to a stationary flashing light spot before, during, and after microiontophoretic application of antagonists and agonists to EAA receptors. 2. The visual response of the lagged cells could be almost completely blocked by an antagonist to the N-methyl-D-aspartate (NMDA) receptor. The degree of suppression was dose dependent, and the average maximum degree of suppression for all the cells was 94%. NMDA enhanced the response, and this enhancement was antagonized by NMDA antagonists. A quisqualate/kainate receptor antagonist had no significant effect on the lagged cells. 3. These findings indicate that the visual response in lagged cells is dependent upon activation of NMDA receptors, which may directly result from activation of retinal inputs. 4. No pharmacologic difference was seen between lagged X- and Y-cells, or between lagged ON- and OFF-center cells. 5. gamma-Aminobutyric acid-A (GABA-A) receptor antagonists were used to study whether the characteristic lag of the visual response and the suppression of the initial transient response component of the lagged cells are dependent on geniculate inhibition. Beside enhancement of the visual response, the GABA antagonists strongly reduced the lag of the visual response, and an initial transient response component occurred instead of the initial suppression. The lag remained slightly longer than for nonlagged cells, and the peak firing rate of the transient was below values typical for nonlagged cells, indicating that the lagged cell properties are dependent on other factors beside GABA-A receptor-mediated inhibition. 6. The enhanced visual response during iontophoresis of GABA antagonists could be completely blocked by simultaneous iontophoresis of an NMDA-receptor antagonist. This gives further support to the hypothesis that the retinal input to these cells is mediated by NMDA receptors. 7. The NMDA-receptor/ionophore complex mediates excitatory postsynaptic potentials (EPSPs) characterized by slow rise and decay times and long duration. The ionophore is characterized by a voltage-dependent blockade that makes these receptors particularly sensitive to inhibitory input. The temporal interplay between the slow NMDA receptor-mediated EPSPs and the fast GABA receptor-mediated inhibitory postsynaptic potentials (IPSPs) may explain the characteristic response properties of the lagged cells.
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Grover, Lawrence M., and Chen Yan. "Evidence for Involvement of Group II/III Metabotropic Glutamate Receptors in NMDA Receptor–Independent Long-Term Potentiation in Area CA1 of Rat Hippocampus." Journal of Neurophysiology 82, no. 6 (December 1, 1999): 2956–69. http://dx.doi.org/10.1152/jn.1999.82.6.2956.
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Previous studies implicated metabotropic glutamate receptors (mGluRs) in N-methyl-d-aspartate (NMDA) receptor–independent long-term potentiation (LTP) in area CA1 of the rat hippocampus. To learn more about the specific roles played by mGluRs in NMDA receptor–independent LTP, we used whole cell recordings to load individual CA1 pyramidal neurons with a G-protein inhibitor [guanosine-5′-O-(2-thiodiphosphate), GDPβS]. Although loading postsynaptic CA1 pyramidal neurons with GDPβS significantly reduced G-protein dependent postsynaptic potentials, GDPβS failed to prevent NMDA receptor– independent LTP, suggesting that postsynaptic G-protein–dependent mGluRs are not required. We also performed a series of extracellular field potential experiments in which we applied group-selective mGluR antagonists. We had previously determined that paired-pulse facilitation (PPF) was decreased during the first 30–45 min of NMDA receptor–independent LTP. To determine if mGluRs might be involved in these PPF changes, we used a twin-pulse stimulation protocol to measure PPF in field potential experiments. NMDA receptor–independent LTP was prevented by a group II mGluR antagonist [(2S)-α-ethylglutamic acid] and a group III mGluR antagonist [(RS)-α-cyclopropyl-4-phosphonophenylglycine], but was not prevented by other group II and III mGluR antagonists [(RS)-α-methylserine-O-phosphate monophenyl ester or (RS)-α-methylserine-O-phosphate]. NMDA receptor–independent LTP was not prevented by either of the group I mGluR antagonists we examined, (RS)-1-aminoindan-1,5-dicarboxylic acid and 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester. The PPF changes which accompany NMDA receptor–independent LTP were not prevented by any of the group-selective mGluR antagonists we examined, even when the LTP itself was blocked. Finally, we found that tetanic stimulation in the presence of group III mGluR antagonists lead to nonspecific potentiation in control (nontetanized) input pathways. Taken together, our results argue against the involvement of postsynaptic group I mGluRs in NMDA receptor–independent LTP. Group II and/or group III mGluRs are required, but the specific details of the roles played by these mGluRs in NMDA receptor–independent LTP are uncertain. Based on the pattern of results we obtained, we suggest that group II mGluRs are required for induction of NMDA receptor–independent LTP, and that group III mGluRs are involved in determining the input specificity of NMDA receptor–independent LTP by suppressing potentiation of nearby, nontetanized synapses.
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Hanada, Takahisa. "Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors." Biomolecules 10, no. 3 (March 18, 2020): 464. http://dx.doi.org/10.3390/biom10030464.
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It is widely accepted that glutamate-mediated neuronal hyperexcitation plays a causative role in eliciting seizures. Among glutamate receptors, the roles of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in physiological and pathological conditions represent major clinical research targets. It is well known that agonists of NMDA or AMPA receptors can elicit seizures in animal or human subjects, while antagonists have been shown to inhibit seizures in animal models, suggesting a potential role for NMDA and AMPA receptor antagonists in anti-seizure drug development. Several such drugs have been evaluated in clinical studies; however, the majority, mainly NMDA-receptor antagonists, failed to demonstrate adequate efficacy and safety for therapeutic use, and only an AMPA-receptor antagonist, perampanel, has been approved for the treatment of some forms of epilepsy. These results suggest that a misunderstanding of the role of each glutamate receptor in the ictogenic process may underlie the failure of these drugs to demonstrate clinical efficacy and safety. Accumulating knowledge of both NMDA and AMPA receptors, including pathological gene mutations, roles in autoimmune epilepsy, and evidence from drug-discovery research and pharmacological studies, may provide valuable information enabling the roles of both receptors in ictogenesis to be reconsidered. This review aimed to integrate information from several studies in order to further elucidate the specific roles of NMDA and AMPA receptors in epilepsy.
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Hartveit, E., and P. Heggelund. "Neurotransmitter receptors mediating excitatory input to cells in the cat lateral geniculate nucleus. II. Nonlagged cells." Journal of Neurophysiology 63, no. 6 (June 1, 1990): 1361–72. http://dx.doi.org/10.1152/jn.1990.63.6.1361.
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1. We studied the type of receptor for excitatory amino acids (EAA) that mediates visual responses of nonlagged cells in the dorsal lateral geniculate nucleus (LGN) by recording the visual response of single cells to a stationary flashing spot before, during, and after iontophoretical application of antagonists and agonists to EAA receptors. 2. The visual response of the nonlagged cells was strongly suppressed, in a dose-dependent manner, by the specific quisqualate/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). The average degree of suppression was 74%. Quisqualate enhanced the visual response. 3. Specific antagonists to the N-methyl-D-aspartate (NMDA) receptor had a weak suppressing effect on most nonlagged cells. The average degree of suppression was 22%. Measurement of such weak effects was complicated by the considerable spontaneous fluctuations of responsivity in the LGN cells. In the majority of cells where the visual response was suppressed by NMDA antagonists, the tonic response component was more strongly suppressed than the initial transient response component. The visual response was enhanced by NMDA, and this enhancement was antagonized by NMDA antagonists. 4. These findings suggest that the excitatory input from the retina to nonlagged LGN cells is mainly mediated by non-NMDA receptors. The non-NMDA receptors mediate fast EPSPs, and this can explain the fast onset and offset of the visual response of the nonlagged cells. 5. The generally small contribution from NMDA receptors to the visual response of the nonlagged cells might reflect a minor involvement of these receptors in the retinal input, or it could be related to the excitatory input to LGN from the visual cortex. 6. To study whether the expression of NMDA receptors was related to modulatory brain stem input to LGN, we examined the effects of the NMDA antagonists when the visual response was enhanced with gamma-aminobutyric acid (GABA) antagonists or acetylcholine (ACh). Neither of these pharmacologic manipulations consistently increased the relative contribution of NMDA receptors to the visual response. 7. No pharmacologic difference was found between nonlagged X- and Y-cells, or between ON- and OFF-center cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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Yuzaki, Michisuke, and John A. Connor. "Characterization of l-Homocysteate–Induced Currents in Purkinje Cells From Wild-Type and NMDA Receptor Knockout Mice." Journal of Neurophysiology 82, no. 5 (November 1, 1999): 2820–26. http://dx.doi.org/10.1152/jn.1999.82.5.2820.
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l-Homocysteic acid (HCA), an endogenous excitatory amino acid in the mammalian CNS, potently activates N-methyl-d-aspartate (NMDA) receptors in hippocampal neurons. However, the responses to HCA in Purkinje cells, which lack functional NMDA receptors, have been largely unexplored: HCA may activate conventional non-NMDA receptors by its mixed agonistic action on both NMDA and non-NMDA receptors, or it may activate a novel non-NMDA receptor that has high affinity for HCA. To test these possibilities, we compared the responses to HCA in cultured Purkinje cells with those in hippocampal neurons by using the whole cell patch-clamp technique. To clearly isolate HCA responses mediated by non-NMDA receptors, we complemented pharmacological methods by using neurons from mutant mice (NR−/−) that lack functional NMDA receptors. A moderate dose of HCA (100 μM) induced substantial responses in Purkinje cells. These responses were blocked by non-NMDA receptor antagonists but were insensitive to NMDA receptor antagonists. HCA also activated responses mediated by non-NMDA receptors in both wild-type and NR1−/− hippocampal neurons. HCA responses in Purkinje cells had a pharmacological profile (EC50 and Hill coefficient) very similar to that of non-NMDA receptor components of HCA responses in hippocampal neurons. Moreover, the amplitude of the non-NMDA receptor component of HCA responses was directly correlated with that of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)– and kainate-induced responses in both types of neurons. Finally, in both types of neurons, HCA currents mediated by non-NMDA receptors were potently blocked by the AMPA receptor antagonist GYKI52466. These findings indicate that HCA-activated AMPA receptors in Purkinje cells are similar to those in hippocampal neurons and that there is no distinct HCA-preferring receptor in Purkinje cells. We also found that in hippocampal neurons, the EC50s of HCA for non-NMDA receptors and for NMDA receptors were more similar than originally reported; this finding indicates that HCA is similar to other mixed agonists, such as glutamate. HCA responses may appear to be selective at NMDA receptors in cells that express these receptors, such as hippocampal neurons; in cells that express few functional NMDA receptors, such as Purkinje cells, HCA may appear to be selective at non-NMDA receptors.
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Homayoun, Houman, Mark E. Jackson, and Bita Moghaddam. "Activation of Metabotropic Glutamate 2/3 Receptors Reverses the Effects of NMDA Receptor Hypofunction on Prefrontal Cortex Unit Activity in Awake Rats." Journal of Neurophysiology 93, no. 4 (April 2005): 1989–2001. http://dx.doi.org/10.1152/jn.00875.2004.
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Systemic exposure to N-methyl-d-aspartate (NMDA) receptor antagonists can lead to psychosis and prefrontal cortex (PFC)–dependent behavioral impairments. Agonists of metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate the adverse behavioral effects of NMDA antagonists in humans and laboratory animals, and are being considered as a novel treatment for some symptoms of schizophrenia. Despite the compelling behavioral data, the cellular mechanisms by which potentiation of mGlu2/3 receptor function attenuates the effects of NMDA receptor hypofunction remain unclear. In freely moving rats, we recorded the response of medial PFC (prelimbic) single units to treatment with the NMDA antagonist MK801 and assessed the dose-dependent effects of pre- or posttreatment with the mGlu2/3 receptor agonist LY354740 on this response. NMDA receptor antagonist-induced behavioral stereotypy was measured during recording because it may relate to the psychotomimetic properties of this treatment and is dependent on the functional integrity of the PFC. In most PFC neurons, systemic administration of MK801 increased the spontaneous firing rate, decreased the variability of spike trains, and disrupted patterns of spontaneous bursts. Given alone, LY354740 (1, 3, and 10 mg/kg) decreased spontaneous activity of PFC neurons at the highest dose. Pre- or posttreatment with LY354740 blocked MK801-induced changes on firing rate, burst activity, and variability of spike activity. These physiological changes coincided with a reduction in MK801-induced behavioral stereotypy by LY354740. These data indicate that activation of mGlu2/3 receptors reduces the disruptive effects of NMDA receptor hypofunction on the spontaneous spike activity and bursting of PFC neurons. This mechanism may provide a physiological basis for reversal of NMDA antagonist-induced behaviors by mGlu2/3 agonists.
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Bryant, Camron D., Shoshana Eitan, Kevin Sinchak, Michael S. Fanselow, and Christopher J. Evans. "NMDA receptor antagonism disrupts the development of morphine analgesic tolerance in male, but not female C57BL/6J mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 2 (August 2006): R315—R326. http://dx.doi.org/10.1152/ajpregu.00831.2005.
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Multiple studies demonstrate that coadministration of N-methyl-d-aspartate (NMDA) receptor antagonists with the opioid agonist morphine attenuates the development of analgesic tolerance. Sex differences in the effects of noncompetitive, but not competitive NMDA receptor antagonists on acute morphine analgesia, have been reported in mice, yet the role of sex in modulation of morphine tolerance by NMDA receptor antagonists has yet to be addressed. Therefore, we tested whether there is a sex difference in the effect of NMDA receptor antagonists on the development of morphine analgesic tolerance in C57BL/6J mice. Acutely, at a dose required to affect morphine tolerance in male mice, the noncompetitive NMDA receptor antagonist dizocilpine (MK-801) prolonged morphine analgesia similarly in both sexes in the hot plate and tail withdrawal assays. In the hot plate assay, coadministration of MK-801 or the competitive antagonist 3-(2-carboxpiperazin-4-yl)propyl-1-phosphanoic acid (CPP) with morphine attenuated the development of tolerance in male mice, while having no effect in females. Like normal and sham females, ovariectomized mice were similarly insensitive to the attenuation of morphine tolerance by MK-801 in the hot plate assay. Surprisingly, in the tail withdrawal assay, MK-801 facilitated the development of morphine-induced hyperalgesia and tolerance in males but not females. The results demonstrate that male mice are more sensitive to modulation of nociception and morphine analgesia after repeated coadministration of NMDA receptor antagonists. Furthermore, the underlying mechanisms are likely to be different from those mediating the sex difference in the modulation of acute morphine analgesia that has previously been reported.
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Butcher, Kenneth S., and David F. Cechetto. "Receptors in lateral hypothalamic area involved in insular cortex sympathetic responses." American Journal of Physiology-Heart and Circulatory Physiology 275, no. 2 (August 1, 1998): H689—H696. http://dx.doi.org/10.1152/ajpheart.1998.275.2.h689.
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Previous evidence has shown that sympathetic nerve responses to insular cortical (IC) stimulation are mediated by synapses within the lateral hypothalamic area (LHA) and ventrolateral medulla. The present study determined the receptor(s) involved at the synapse in the LHA associated with stimulation-evoked IC sympathetic responses. Twenty-seven male Wistar rats were instrumented for renal nerve activity, arterial pressure, and heart rate recording. The right IC was stimulated with a bipolar electrode (200–1,000 μA, 2 ms, 0.8 Hz) resulting in sympathetic nerve responses. Antagonists were then pressure injected into the ipsilateral LHA (300–500 nl). Kynurenate (250 mM) injections resulted in 51 ± 8% (range 0–100%) block of IC-stimulated sympathetic nerve responses. Similarly, the N-methyl-d-aspartic acid (NMDA)-receptor antagonistdl-2-amino-5-phosphonopentanoic acid (200 μM) resulted in an inhibition (82 ± 8%; range 51–100%) of IC-stimulated sympathetic responses. Injection of the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (200 μM) had no effect on IC sympathetic responses. Injection of antagonists to GABA, acetylcholine, and adrenergic receptors was also without effect. No antagonist injections had any effects on baseline sympathetic nerve discharge, arterial pressure, or heart rate. These results suggest that the IC autonomic efferents projecting to the LHA utilize NMDA glutamatergic receptors.
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Soltis, R. P., and J. A. DiMicco. "Interaction of hypothalamic GABAA and excitatory amino acid receptors controlling heart rate in rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 261, no. 2 (August 1, 1991): R427—R433. http://dx.doi.org/10.1152/ajpregu.1991.261.2.r427.
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We have previously shown that microinjection of drugs that impair gamma-aminobutyric acid (GABA)-mediated synaptic inhibition into the dorsomedial hypothalamus (DMH) of rats generates cardiovascular and behavioral changes that mimic the response to stress. The purpose of this study was to examine the role of excitatory amino acid (EAA) receptors in the DMH in generating the cardiovascular changes caused by withdrawal of local GABAergic inhibition in urethan-anesthetized rats. Local treatment of the DMH with the nonselective EAA antagonist kynurenic acid blocked or reversed the increases in heart rate and blood pressure caused by microinjection of the GABAA antagonists bicuculline methiodide (BMI) or picrotoxin into the same region. Conversely, similar injection of xanthurenic acid, a structural analogue of kynurenic acid without significant effects on EAA receptors, did not significantly alter the cardiovascular changes produced by either GABAA antagonist. The tachycardic effects of BMI were also attenuated by injection of either the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid or the non-NMDA EAA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. When the two EAA receptor antagonists were combined, their effects to suppress the BMI-induced tachycardia were additive. These findings suggest that the cardiovascular effects caused by blockade of GABAergic inhibition in the DMH of the rat are dependent on activation of local NMDA and non-NMDA EAA receptors.
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Thompson, Trevor, Fiona Whiter, Katy Gallop, Nicola Veronese, Marco Solmi, Paul Newton, and Brendon Stubbs. "NMDA receptor antagonists and pain relief." Neurology 92, no. 14 (March 6, 2019): e1652-e1662. http://dx.doi.org/10.1212/wnl.0000000000007238.
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ObjectiveWe conducted a meta-analysis of controlled trials that used experimental models of acute pain and hyperalgesia to examine the analgesic effects of NMDA receptor (NMDAR) antagonists.MethodsSix major databases were systematically searched (to March 2018) for studies using human evoked pain models to compare NMDAR antagonists with no-intervention controls. Pain outcome data were analyzed with random-effects meta-analysis.ResultsSearches identified 70 eligible trials (n = 1,069). Meta-analysis found that low-dose ketamine (<1 mg/kg) produced a decrease in hyperalgesic area (standardized mean difference 0.54, 95% confidence interval [CI] 0.34, 0.74,p< 0.001) and a 1.2-point decrease (95% CI 0.88, 1.44,p< 0.001) in pain ratings from 4.6 to 3.4 on a 0–10 scale (a 26% reduction). Similar analgesia was observed for acute and hyperalgesic models and was constant across the dosing range (0.03–1.00 mg/kg). Moderate to high variability in effect size was observed and mild side effects (e.g., sedation, sensory disturbance) were common. No effects of dextromethorphan were found.ConclusionsFindings provide robust evidence for analgesic and antihyperalgesic effects of ketamine, supporting its utility for acute and chronic pain management. However, pain relief was modest, suggesting ketamine may potentially be most useful when opioids are contraindicated, rapid analgesia is required, or for pain resistant to conventional medication.
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Radenovic, Lidija, Vesna Selakovic, Branka Janac, and Dajana Todorovic. "Effect of glutamate antagonists on nitric oxide production in rat brain following intrahippocampal injection." Archives of Biological Sciences 59, no. 1 (2007): 29–36. http://dx.doi.org/10.2298/abs0701029r.
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Stimulation of glutamate receptors induces neuronal nitric oxide (NO) release, which in turn modulates glutamate transmission. The involvement of ionotropic glutamate NMDA and AMPA/kainate receptors in induction of NO production in the rat brain was examined after injection of kainate, a non-NMDA receptor agonist; kainate plus 6-cyano- 7-nitroquinoxaline-2,3-dione (CNQX), a selective AMPA/kainate receptor antagonist; or kainate plus 2-amino-5-phosphonopentanoic acid (APV), a selective NMDA receptor antagonist. Competitive glutamate receptor antagonists were injected with kainate unilaterally into the CA3 region of the rat hippocampus. The accumulation of nitrite, the stable metabolite of NO, was measured by the Griess reaction at different times (5 min, 15 min, 2 h, 48 h, and 7 days) in hippocampus, forebrain cortex, striatum, and cerebellum homogenates. The used glutamate antagonists APV and CNQX both provided sufficient neuroprotection in the sense of reducing nitrite concentrations, but with different mechanisms and time dynamics. Our findings suggest that NMDA and AMPA/kainate receptors are differentially involved in nitric oxide production. <br><br><font color="red"><b> This article has been retracted. Link to the retraction <u><a href="http://dx.doi.org/10.2298/ABS150319031E">10.2298/ABS150319031E</a><u></b></font>
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Pogatzki, Esther M., Peter K. Zahn, and Timothy J. Brennan. "Effect of Pretreatment with Intrathecal Excitatory Amino Acid Receptor Antagonists on the Development of Pain Behavior Caused by Plantar Incision." Anesthesiology 93, no. 2 (August 1, 2000): 489–96. http://dx.doi.org/10.1097/00000542-200008000-00029.
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Background Drugs that block spinal excitatory amino acid receptor activation may prevent pain after surgery. The authors previously studied the effect of excitatory amino acid receptor antagonists after incision. In the present study, we examined the role of N-methyl-d-aspartate (NMDA), non-NMDA, and metabotropic glutamate receptors (mGluRs) on the development of pain behavior after plantar incision. Methods Rats with lumbar intrathecal catheters were anesthetized with halothane. Fifteen minutes before an incision was made, drug [40 nmol MK-801; 20 nmol NBQX; or 200 nmol (+)-MCPG] or vehicle was injected intrathecally followed by an infusion of the same drug for 75 min. Withdrawal thresholds to calibrated von Frey filaments applied adjacent to the wound and response frequencies to a blunt mechanical stimulus applied directly to the wound were measured before incision and 1, 2, 4, and 6 h after incision and then once daily for 6 days. Results Preincision treatments with antagonists against the NMDA (MK-801) and group I and II metabotropic receptors [(+)-MCPG] did not inhibit the development of mechanical hyperalgesia caused by incision. Preincision treatment with the non-NMDA receptor antagonist NBQX increased withdrawal thresholds at 1 and 2 h and on postoperative day 1 compared with the vehicle group; response frequencies were reduced 1 and 2 h after incision and on postoperative day 2 (P < 0.05). In an additional group, postincision treatment with NBQX was similar to preincision treatment. Conclusion Spinal NMDA and mGluR antagonists may not be useful for preventing postsurgical pain. Spinal non-NMDA receptor antagonists reduced pain behaviors, but a preventive effect using preincision treatment was not apparent.
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Karius, D. R., L. Ling, and D. F. Speck. "Nucleus tractus solitarius and excitatory amino acids in afferent-evoked inspiratory termination." Journal of Applied Physiology 76, no. 3 (March 1, 1994): 1293–301. http://dx.doi.org/10.1152/jappl.1994.76.3.1293.
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This study tested the hypothesis that excitatory amino acid (EAA) neurotransmission at non-N-methyl-D-aspartate (non-NMDA), but not NMDA, receptors within medial regions of the nucleus tractus solitarius (NTS) is required in the inspiratory termination elicited by vagal or intercostal nerve (ICN) stimulation. Adult cats were anesthetized, decerebrated, vagotomized, and ventilated. After control responses to stimulation of the superior laryngeal nerve (SLN), vagus, and ICN were obtained, EAA receptor antagonists were injected into the medial aspects of the NTS. Injections of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or 6,7-dinitro-quinoxaline-2,3-dione (DNQX), EAA receptor antagonists; (+/-)-2-amino-5-phosphonopentanoic acid (AP5), an NMDA antagonist; or 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), a non-NMDA antagonist, ipsilateral to the vagus abolished the termination response. The SLN-elicited response persisted after AP5 injection but was abolished by NBQX injections. The ICN-elicited response persisted after bilateral injections of CNQX/DNQX or procaine. We conclude that the inspiratory termination elicited by ICN stimulation is independent of the regions medial to the NTS. Inspiratory termination elicited by vagal or SLN stimulation requires non-NMDA-mediated EAA neurotransmission within medial aspects of the NTS, but the vagally elicited response also requires NMDA receptors.
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Radenovic, Lidija, and Vesna Selakovic. "Mitochondrial superoxide production and MnSOD activity following exposure to an agonist and antagonists of ionotropic receptors in rat brain." Archives of Biological Sciences 57, no. 1 (2005): 1–10. http://dx.doi.org/10.2298/abs0501001r.
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The involvement of NMDA and AMPA/kainate receptors in the induction of superoxide production in the rat brain was examined after intrahippocampal injection of kainate, a non-NMDA receptor agonist; kainate plus CNQX, a selective AMPA/kainate receptor antagonist; or kainate plus APV, a selective NMDA receptor antagonist. The measurements took place at different times in the ipsi- and contralateral hippocampus, forebrain cortex, striatum, and cerebellum homogenates. The used glutamate antagonists both ensured sufficient neuroprotection in the sense of lowering superoxide production and raising MnSOD levels, but in the mechanisms and time dynamics of their effects were different. Our findings suggest that NMDA and AMPA/kainate receptors are differentially involved in superoxide production. <br><br><font color="red"><b> This article has been retracted. Link to the retraction <u><a href="http://dx.doi.org/10.2298/ABS150318026E">10.2298/ABS150318026E</a><u></b></font>
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Nakano, Tomosuke, Toshiki Hasegawa, Dai Suzuki, Eishi Motomura, and Motohiro Okada. "Amantadine Combines Astroglial System Xc− Activation with Glutamate/NMDA Receptor Inhibition." Biomolecules 9, no. 5 (May 17, 2019): 191. http://dx.doi.org/10.3390/biom9050191.
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A glutamate/NMDA receptor (NMDA-R) antagonist, amantadine (AMA) exhibits a broad spectrum of clinically important properties, including antiviral, antiparkinsonian, neuroprotective, neuro-reparative and cognitive-enhancing effects. However, both clinical and pre-clinical studies have demonstrated that noncompetitive NMDA-R antagonists induce severe schizophrenia-like cognitive deficits. Therefore, this study aims to clarify the clinical discrepancy between AMA and noncompetitive NMDA-R antagonists by comparing the effects of AMA with those of a noncompetitive NMDA-R antagonist, MK801, on rat tripartite glutamatergic synaptic transmission using microdialysis and primary cultured astrocytes. Microdialysis study demonstrated that the stimulatory effects of AMA on L-glutamate release differed from those of MK801 in the globus pallidus, entorhinal cortex and entopeduncular nucleus. The stimulatory effect of AMA on L-glutamate release was modulated by activation of cystine/glutamate antiporter (Sxc). Primary cultured astrocytes study demonstrated that AMA also enhanced glutathione synthesis via Sxc activation. Furthermore, carbon-monoxide induced damage of the astroglial glutathione synthesis system was repaired by AMA but not MK801. Additionally, glutamate/AMPA receptor (AMPA-R) antagonist, perampanel enhanced the protective effects of AMA. The findings of microdialysis and cultured astrocyte studies suggest that a combination of Sxc activation with inhibitions of ionotropic glutamate receptors contributes to neuroprotective, neuro-reparative and cognitive-enhancing activities that can mitigate several neuropsychiatric disorders.
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Do, Viet H., Carlo O. Martinez, Joe L. Martinez, and Brian E. Derrick. "Long-Term Potentiation in Direct Perforant Path Projections to the Hippocampal CA3 Region In Vivo." Journal of Neurophysiology 87, no. 2 (February 1, 2002): 669–78. http://dx.doi.org/10.1152/jn.00938.2000.
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The perforant path constitutes the primary projection system relaying information from the neocortex to the hippocampal formation. Long-term synaptic potentiation (LTP) in the perforant path projections to the dentate gyrus is well characterized. However, surprisingly few studies have addressed the mechanisms underlying LTP induction in the direct perforant path projections to the hippocampus. Here we investigate the role of N-methyl-d-aspartate (NMDA) and opioid receptors in the induction of LTP in monosynaptic medial and lateral perforant path projections to the CA3 region in adult pentobarbital sodium–anesthetized rats. Similar to LTP observed at the medial perforant path–dentate gyrus synapse, medial perforant path–CA3 synapses display LTP that is blocked by both local and systemic administration of the competitive NMDA receptor antagonist (±)-3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid [(±)-CPP]. By contrast, LTP induced at the lateral perforant path–CA3 synapses is not blocked by either local or systemic administration of this NMDA receptor antagonist. The induction of LTP at lateral perforant path–CA3 synapses, which is blocked by the opioid receptor antagonist naloxone, is also blocked by the selective mu (μ) opioid receptor antagonist Cys2-Tyr3-Orn5-Pen7-amide (CTOP), but not the selective delta (δ) opioid receptor antagonist naltrindole (NTI). CTOP was without effect on the induction of medial perforant path–CA3 LTP. The selective sensitivity of lateral perforant path–CA3 LTP to μ-opioid receptor antagonists corresponds with the distribution of μ-opioid receptors within the stratum lacunosum-moleculare of area CA3 where perforant path projections to CA3 terminate. These data indicate that both lateral and medial perforant path projections to the CA3 region display LTP, and that LTP induction in medial and lateral perforant path–CA3 synapses are differentially sensitive to NMDA receptor and μ-opioid receptor antagonists. This suggests a role for opioid, but not NMDA receptors in the induction of LTP at lateral perforant path projections to the hippocampal formation.
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Nikam, Sham, and Leonard Meltzer. "NR2B Selective NMDA Receptor Antagonists." Current Pharmaceutical Design 8, no. 10 (May 1, 2002): 845–55. http://dx.doi.org/10.2174/1381612024607072.
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Catarzi, Daniela, Vittoria Colotta, and Flavia Varano. "Competitive Gly/NMDA Receptor Antagonists." Current Topics in Medicinal Chemistry 6, no. 8 (April 1, 2006): 809–21. http://dx.doi.org/10.2174/156802606777057544.
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PALMER, GENE C., JERRY A. MILLER, EDWARD F. CREGAN, PATRICIA GENDRON, and JAMES PEELING. "Low-Affinity NMDA Receptor Antagonists." Annals of the New York Academy of Sciences 825, no. 1 Neuroprotecti (October 1997): 220–31. http://dx.doi.org/10.1111/j.1749-6632.1997.tb48432.x.
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Kikuchi, Tetsuro. "Is Memantine Effective as an NMDA Receptor Antagonist in Adjunctive Therapy for Schizophrenia?" Biomolecules 10, no. 8 (July 31, 2020): 1134. http://dx.doi.org/10.3390/biom10081134.
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Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist approved for treating Alzheimer’s disease, has a good safety profile and is increasingly being studied for possible use in a variety of non-dementia psychiatric disorders. There is an abundance of basic and clinical data that support the hypothesis that NMDA receptor hypofunction contributes to the pathophysiology of schizophrenia. However, there are numerous randomized, double-blind, placebo-controlled clinical trials showing that add-on treatment with memantine improves negative and cognitive symptoms, particularly the negative symptoms of schizophrenia, indicating that memantine as adjunctive therapy in schizophrenia helps to ameliorate negative symptoms and cognitive deficits. It remains unclear why memantine does not show undesirable central nervous system (CNS) side effects in humans unlike other NMDA receptor antagonists, such as phencyclidine and ketamine. However, the answer could lie in the fact that it would appear that memantine works as a low-affinity, fast off-rate, voltage-dependent, and uncompetitive antagonist with preferential inhibition of extrasynaptic receptors. It is reasonable to assume that the effects of memantine as adjunctive therapy on negative symptoms and cognitive deficits in schizophrenia may derive primarily, if not totally, from its NMDA receptor antagonist activity at NMDA receptors including extrasynaptic receptors in the CNS.
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Sharp, Christopher D., I. Hines, J. Houghton, A. Warren, T. H. Jackson, A. Jawahar, A. Nanda, et al. "Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 6 (December 2003): H2592—H2598. http://dx.doi.org/10.1152/ajpheart.00520.2003.
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l-Glutamate is a major excitatory neurotransmitter that binds ionotropic and metabotropic glutamate receptors. Cerebral endothelial cells from many species have been shown to express several forms of glutamate receptors; however, human cerebral endothelial cells have not been shown to express either the N-methyl-d-aspartate (NMDA) receptor message or protein. This study provides evidence that human cerebral endothelial cells express the message and protein for NMDA receptors. Human cerebral endothelial cell monolayer electrical resistance changes in response to glutamate receptor agonists, antagonists, and second message blockers were tested. RT-PCR and Western blot analysis were used to demonstrate the presence of the NMDA receptor. Glutamate and NMDA (1 mM) caused a significant decrease in electrical resistance compared with sham control at 2 h postexposure; this response could be blocked significantly by MK-801 (an NMDA antagonist), 8-( N,N-diethylamino)- n-octyl-3,4,5-trimethyoxybenzoate (an intracellular Ca2+antagonist), and N-acetyl-l-cystein (an antioxidant). Trans(±)-1-amino-1,3-cyclopentanedicarboxylic acid, a metabotropic receptor agonist (1 mM), did not significantly decrease electrical resistance. Our results are consistent with a model where glutamate, at excitotoxic levels, may lead to a breakdown in the blood brain barrier via activation of NMDA receptors.
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Hada, Binika, Mrigendra Bir Karmacharya, So R. Park, and Byung H. Choi. "Low-Intensity Ultrasound Decreases Ischemia-Induced Edema by Inhibiting N-Methyl-d-Aspartic Acid Receptors." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, no. 6 (November 2018): 675–81. http://dx.doi.org/10.1017/cjn.2018.331.
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AbstractBackground: We have previously shown that low-intensity ultrasound (LIUS), a noninvasive mechanical stimulus, inhibits brain edema formation induced by oxygen and glucose deprivation (OGD) or treatment with glutamate, a mediator of OGD-induced edema, in acute rat hippocampal slice model in vitro. Methods: In this study, we treated the rat hippocampal slices with N-methyl-d-aspartic acid (NMDA) or (S)-3,5-dihydroxyphenylglycine (DHPG) to determine whether these different glutamate receptor agonists induce edema. The hippocampal slices were then either sonicated with LIUS or treated with N-methyl-d-aspartic acid receptor (NMDAR) antagonists, namely, MK-801 and ketamine, and observed their effects on edema formation. Results: We observed that treatment with NMDA, an agonist of ionotropic glutamate receptors, induced brain edema at similar degrees compared with that induced by OGD. However, treatment with DHPG, an agonist of metabotropic glutamate receptors, did not significantly induce brain edema. Treatment with the NMDAR antagonists MK-801 or ketamine efficiently prevented brain edema formation by both OGD and NMDA in a concentration-dependent manner. N-Methyl-d-aspartic acid-induced brain edema was alleviated by LIUS in an intensity-dependent manner when ultrasound was administered at 30, 50, or 100 mW/cm2 for 20 minutes before the induction of the edema. Furthermore, LIUS reduced OGD- and NMDA-induced phosphorylation of NMDARs at Y1325. Conclusion: These results suggest that LIUS can inhibit OGD- or NMDA-induced NMDAR activation by preventing NMDAR phosphorylation, thereby reducing a subsequent brain edema formation. The mechanisms by which LIUS inhibits NMDAR phosphorylation need further investigation.
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Rogawski, Michael A. "The NMDA Receptor, NMDA Antagonists and Epilepsy Therapy." Drugs 44, no. 3 (September 1992): 279–92. http://dx.doi.org/10.2165/00003495-199244030-00001.
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Kabir, Md Tanvir, Mohammad A. Sufian, Md Sahab Uddin, Mst Marium Begum, Shammi Akhter, Ariful Islam, Bijo Mathew, Md Siddiqul Islam, Md Shah Amran, and Ghulam Md. Ashraf. "NMDA Receptor Antagonists: Repositioning of Memantine as a Multitargeting Agent for Alzheimer's Therapy." Current Pharmaceutical Design 25, no. 33 (November 19, 2019): 3506–18. http://dx.doi.org/10.2174/1381612825666191011102444.
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: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes problems with memory, thinking, and behavior. Currently, there is no drug that can reduce the pathological events of this degenerative disease but symptomatic relief is possible that can abate the disease condition. N-methyl-D-aspartate (NMDA) receptors exert a critical role for synaptic plasticity as well as transmission. Overstimulation of glutamate receptors, predominantly NMDA type, may cause excitotoxic effects on neurons and is recommended as a mechanism for neurodegeneration. Atypical activation of the NMDA receptor has been suggested for AD by synaptic dysfunction. NMDA receptor antagonists especially memantine block the NMDA receptor and can reduce the influx of calcium (Ca2+) ions into neuron, thus, toxic intracellular events are not activated. This review represents the role of NMDA receptors antagonists as potential therapeutic agents to reduce AD. Moreover, this review highlights the repositioning of memantine as a potential novel therapeutic multitargeting agent for AD.
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Cairns, Brian E., Peter Svensson, Kelun Wang, Steen Hupfeld, Thomas Graven-Nielsen, Barry J. Sessle, Charles B. Berde, and Lars Arendt-Nielsen. "Activation of Peripheral NMDA Receptors Contributes to Human Pain and Rat Afferent Discharges Evoked by Injection of Glutamate into the Masseter Muscle." Journal of Neurophysiology 90, no. 4 (October 2003): 2098–105. http://dx.doi.org/10.1152/jn.00353.2003.
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Peripheral N-methyl-d-aspartate (NMDA) receptors are found in deep tissues and may play a role in deep tissue pain. Injection of the endogenous NMDA receptor agonist glutamate into the masseter muscle excites deep craniofacial afferent fibers in rats and evokes pain in human subjects. It is not clear whether peripheral NMDA receptors play a role in these effects of glutamate. Accordingly, the effect of NMDA on afferent activity as well as the effect of locally administered NMDA receptor antagonists on glutamate-evoked afferent discharges in acutely anesthetized rats and muscle pain in human subjects was examined. Injection of NMDA into the masseter muscle evoked afferent discharges in a concentration-related manner. It was found that the NMDA receptor antagonists 2-amino-5-phosphonvalerate (APV, 10 mM), ketamine (10 mM), and dextromethorphan (40 mM) significantly decreased glutamate-evoked afferent discharges. The effects of APV and ketamine, but not dextromethorphan, were selective for glutamate-evoked afferent discharges and did not affect hypertonic saline-evoked afferent discharges. In human experiments, it was found that 10 mM ketamine decreased glutamate-evoked muscle pain but had no effect on hypertonic saline-evoked muscle pain. These results indicate that injection of glutamate into the masseter muscle evokes afferent discharges in rats and muscle pain in humans in part through activation of peripheral NMDA receptors. It is conceivable that activation of peripheral NMDA receptors may contribute to masticatory muscle pain and that peripherally acting NMDA receptor antagonists could prove to be effective analgesics for this type of pain.
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Benveniste, M., J. M. Mienville, E. Sernagor, and M. L. Mayer. "Concentration-jump experiments with NMDA antagonists in mouse cultured hippocampal neurons." Journal of Neurophysiology 63, no. 6 (June 1, 1990): 1373–84. http://dx.doi.org/10.1152/jn.1990.63.6.1373.
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1. Voltage-clamp experiments were used to study N-methyl-D-aspartic acid (NMDA) receptor antagonists applied by fast perfusion to mouse hippocampal neurons in dissociated culture. 2. Preincubation with the NMDA antagonists zinc (3-30 microM) and magnesium (30-300 microM) reduced subsequent responses to 100 microM NMDA applied together with these antagonists. No time dependence of antagonism was observed when responses were measured at the start and at the end of NMDA pulses 1.25-1.5 s in duration. 3. Two competitive antagonists of similar affinity in equilibrium experiments, D-2-amino-5-phosphonopentanoic acid (D-AP5) and 3-((+-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), had different profiles of action when applied as described above. With D-AP5, pulses of NMDA produced fast-on, fast-off responses, of reduced amplitude, similar to the effect of Zn and Mg. Responses to NMDA in the presence of CPP were also of reduced amplitude but, in addition, showed slow activation, such that the antagonist action of CPP decreased with time after the application of NMDA. 4. In the presence of 3 microM glycine and NMDA receptor antagonists with activity at the glycine modulatory site, either kynurenic acid (Kyn), 7-chlorokynurenic acid (7Cl-Kyn), or 5-chloro-indole-2-carboxylic acid (5Cl-I2CA), NMDA-evoked responses showed apparent use-dependent antagonism, such that the peak response to NMDA was much greater than the equilibrium response. A similar effect was produced by preincubation with low concentrations of glycine (less than 300 nM), which enhances desensitization of responses to NMDA. The apparent use-dependent action of glycine antagonists could be reversed on raising the glycine concentration and did not vary appreciably with changes in membrane potential over the range -60 to +50 mV. 5. Concentration-jump application of NMDA antagonists, in the presence of 100 microM NMDA and 3 microM glycine, were used to study antagonist association and dissociation kinetics directly. For D-AP5 and CPP, the dissociation rate was independent of antagonist concentration, and approximately 15 times faster for D-AP5 (19.6 s-1) than for CPP (1.36 s-1). The association rate for D-AP5 and CPP increased with antagonist concentration in a linear manner over the range 3-30 microM and was slower for CPP than for D-AP5, consistent with their similar potency at equilibrium. 6. In contrast to results obtained with CPP and D-AP5, the association rate for 7Cl-Kyn was approximately 3 times slower than the dissociation rate and did not change with concentration of antagonist.(ABSTRACT TRUNCATED AT 400 WORDS)
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Wright, Jason, Carlos Campos, Thiebaut Herzog, Mihai Covasa, Krzysztof Czaja, and Robert C. Ritter. "Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 301, no. 2 (August 2011): R448—R455. http://dx.doi.org/10.1152/ajpregu.00026.2011.
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Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.
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Nishiyama, Tomoki, Tony L. Yaksh, and Eckard Weber. "Effects of Intrathecal NMDA and Non-NMDA Antagonists on Acute Thermal Nociception and Their Interaction with Morphine." Anesthesiology 89, no. 3 (September 1, 1998): 715–22. http://dx.doi.org/10.1097/00000542-199809000-00023.
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Background N-methyl-D-aspartate (NDMA) antagonists have minimal effects on acute nociception but block facilitated states of processing. In contrast, the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists decrease acute noxious responses. Morphine (a mu-opioid agonist) can also decrease acute nociceptive processing. The authors hypothesized that the interaction between morphine and AMPA receptor antagonists would be synergistic, whereas morphine and NMDA antagonists show no such interaction in acute nociception. Methods Sprague-Dawley rats (weight, 250-300 g) were implanted with chronic lumbar intrathecal catheters and were assigned to receive one of several doses of morphine--ACEA 1021 (NMDA glycine site antagonist), ACEA 2085 (AMPA antagonist), AP-5 (NMDA antagonist), saline or vehicle--and were tested for their effect on the response latency using a 52.5 degrees C hot plate. The combinations of morphine and other agents also were tested. Results Intrathecal morphine (ED50:2 microg/95% confidence interval, 1-4 microg) and ACEA 2085 (6 ng/2-15 ng), but not AP-5 or ACEA 1021, yielded a dose-dependent increase in the thermal escape latency. A systematic isobolographic analysis was carried out between intrathecal morphine and ACEA 2085 using the ED50 dose ratio of 357:1. A potent synergy was observed with decreased side effects. Morphine dose-response curves were carried out for morphine and fixed doses of ACEA 1021 (12 microg) or AP-5 (10 microg). No synergistic interactions were noted. Conclusions Spinal mu-receptor activation and AMPA receptor antagonism showed a synergistic antinociception in response to an acute thermal stimulus. NMDA or NMDA glycine site antagonism had no effect alone nor did they display synergy with morphine. These results suggest an important direction for development of acute pain strategies may focus on the AMPA receptor.
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Ding, Fei, Yunpeng Bai, Qiong Cheng, Shu Yu, Mengchun Cheng, Yulin Wu, Xiaozhe Zhang, Xinmiao Liang, and Xiaosong Gu. "Bidentatide, a Novel Plant Peptide Derived from Achyranthes bidentata Blume: Isolation, Characterization, and Neuroprotection through Inhibition of NR2B-Containing NMDA Receptors." International Journal of Molecular Sciences 22, no. 15 (July 26, 2021): 7977. http://dx.doi.org/10.3390/ijms22157977.
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Increasing attention is being focused on the use of polypeptide-based N-methyl-d-aspartate (NMDA) receptor antagonists for the treatment of nervous system disorders. In our study on Achyranthes bidentata Blume, we identified an NMDA receptor subtype 2B (NR2B) antagonist that exerts distinct neuroprotective actions. This antagonist is a 33 amino acid peptide, named bidentatide, which contains three disulfide bridges that form a cysteine knot motif. We determined the neuroactive potential of bidentatide by evaluating its in vitro effects against NMDA-mediated excitotoxicity. The results showed that pretreating primary cultured hippocampal neurons with bidentatide prevented NMDA-induced cell death and apoptosis via multiple mechanisms that involved intracellular Ca2+ inhibition, NMDA current inhibition, and apoptosis-related protein expression regulation. These mechanisms were all dependent on bidentatide-induced inhibitory regulation of NR2B-containing NMDA receptors; thus, bidentatide may contribute to the development of neuroprotective agents that would likely possess the high selectivity and safety profiles inherent in peptide drugs.
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Adell, Albert. "Brain NMDA Receptors in Schizophrenia and Depression." Biomolecules 10, no. 6 (June 23, 2020): 947. http://dx.doi.org/10.3390/biom10060947.
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N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both in animals and humans. However, ketamine has been recently approved for treatment-resistant depression, although with severe restrictions. Interestingly, the dosage in both conditions is similar, and positive symptoms of schizophrenia appear before antidepressant effects emerge. Here, we describe the temporal mechanisms implicated in schizophrenia-like and antidepressant-like effects of NMDA blockade in rats, and postulate that such effects may indicate that NMDA receptor antagonists induce similar mechanistic effects, and only the basal pre-drug state of the organism delimitates the overall outcome. Hence, blockade of NMDA receptors in depressive-like status can lead to amelioration or remission of symptoms, whereas healthy individuals develop psychotic symptoms and schizophrenia patients show an exacerbation of these symptoms after the administration of NMDA receptor antagonists.
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Sulkowski, Grzegorz, Beata Dąbrowska-Bouta, and Lidia Strużyńska. "Modulation of Neurological Deficits and Expression of Glutamate Receptors during Experimental Autoimmune Encephalomyelitis after Treatment with Selected Antagonists of Glutamate Receptors." BioMed Research International 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/186068.
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The aim of our investigation was to characterize the role of group I mGluRs and NMDA receptors in pathomechanisms of experimental autoimmune encephalomyelitis (EAE), the rodent model of MS. We tested the effects of LY 367385 (S-2-methyl-4-carboxyphenylglycine, a competitive antagonist of mGluR1), MPEP (2-methyl-6-(phenylethynyl)-pyridine, an antagonist of mGluR5), and the uncompetitive NMDA receptor antagonists amantadine and memantine on modulation of neurological deficits observed in rats with EAE. The neurological symptoms of EAE started at 10-11 days post-injection (d.p.i.) and peaked after 12-13 d.p.i. The protein levels of mGluRs and NMDA did not increase in early phases of EAE (4 d.p.i.), but starting from 8 d.p.i. to 25 d.p.i., we observed a significant elevation of mGluR1 and mGluR5 protein expression by about 20% and NMDA protein expression by about 10% over the control at 25 d.p.i. The changes in protein levels were accompanied by changes in mRNA expression of group I mGluRs and NMDARs. During the late disease phase (20–25 d.p.i.), the mRNA expression levels reached 300% of control values. In contrast, treatment with individual receptor antagonists resulted in a reduction of mRNA levels relative to untreated animals.
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Warner, Michael A., Kenneth H. Neill, J. Victor Nadler, and Barbara J. Crain. "Regionally Selective Effects of NMDA Receptor Antagonists against Ischemic Brain Damage in the Gerbil." Journal of Cerebral Blood Flow & Metabolism 11, no. 4 (July 1991): 600–610. http://dx.doi.org/10.1038/jcbfm.1991.110.
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This study compared the ability of three N-methyl-D-aspartate (NMDA) receptor antagonists to prevent neuronal degeneration in an animal model of global cerebral ischemia. The model employed is characterized by damage to the striatum, hippocampus, and neocortex. Antagonists were administered to gerbils either before or after a 5-min bilateral carotid occlusion. The intraischemic rectal temperature was either maintained at 36–37°C or allowed to fall passively to 28–32°C. Antagonists and doses tested were 1 and 10 mg/kg of MK-801 (pre- or postischemia), 30 mg/kg of CGS 19755 preischemia, four 25 mg/kg doses of CGS 19755 administered between 0.5 and 6.5 h postischemia, and 40 mg/kg of MDL 27,266 (pre- or postischemia). All three NMDA receptor antagonists exhibited some degree of neuroprotective activity when the carotid occlusion was performed under normothermic conditions. Most of the treatments with antagonist markedly reduced striatal damage. CA1 hippocampal and neocortical pyramidal cells were spared by only three of the treatments, however, and the extent of neuroprotection varied widely from case to case. Toxic doses of antagonist were required to protect CA1 pyramidal cells from ischemic damage. Ischemic damage to hippocampal areas CA2–CA3a and CA4 appeared to be resistant to all of these treatments. Most CA1 pyramidal cells that were protected from degeneration by an NMDA receptor antagonist were histologically abnormal. The neuroprotective effects of MK-801 and intraischemic hypothermia appeared to be additive. MK-801 (10 mg/kg) consistently reduced the postischemic brain temperature, but only the magnitude of hypothermia produced soon after reperfusion correlated with its neuroprotective action. These results suggest that NMDA receptor antagonists are relatively poor neuroprotective agents against a moderately severe ischemic insult.
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Zahn, Peter K., and Timothy J. Brennan. "Lack of Effect of Intrathecally Administered N-methyl-D-aspartate Receptor Antagonists in a Rat Model for Postoperative Pain." Anesthesiology 88, no. 1 (January 1, 1998): 143–56. http://dx.doi.org/10.1097/00000542-199801000-00022.
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Background Evidence from experiments by others indicates an important role for excitatory amino acids activating spinal n-methyl-d-aspartate (NMDA) receptors in models of persistent pain. The purpose of this study was to examine the effect of intrathecal (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801), a noncompetitive NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (AP5), a competitive NMDA receptor antagonist, and N-G-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, on pain behaviors in a rat model of postoperative pain. Methods Rats with intrathecal catheters were anesthetized and underwent a plantar incision. Withdrawal threshold to punctate stimulation applied adjacent to the wound, response frequency to application of a nonpunctate stimulus applied directly to the wound, and nonevoked pain behaviors were measured before and after intrathecal administration of MK-801 or AP5. The effect of intrathecal L-NAME on mechanical hyperalgesia was also examined. Results Mechanical hyperalgesia increased and was persistent after plantar incision and was not decreased by intrathecal administration of 4, 14, or 40 nmol MK-801 or 10 nmol AP5. Only the greatest dose of AP5, 30 nmol, caused a small decrease in punctate and nonpunctate hyperalgesia. Intrathecal L-NAME had no effect. Neither intrathecal MK-801 nor intrathecal AP5 affected nonevoked pain behaviors. The greatest doses caused motor deficits. Conclusions Unlike intrathecal and systemic morphine, intrathecal NMDA receptor antagonists did not modify pain behaviors in this rat model of postoperative pain. These data suggest that NMDA receptors do not play an important role in the maintenance of postoperative pain behaviors and that NMDA receptor antagonists, administered spinally by themselves during the postoperative period, will not be useful for the treatment of postoperative pain in humans.
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Anderson, Trent R., and R. David Andrew. "Spreading Depression: Imaging and Blockade in the Rat Neocortical Brain Slice." Journal of Neurophysiology 88, no. 5 (November 1, 2002): 2713–25. http://dx.doi.org/10.1152/jn.00321.2002.
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Spreading depression (SD) is a profound but transient depolarization of neurons and glia that migrates across the cortical and subcortical gray at 2–5 mm/min. Under normoxic conditions, SD occurs during migraine aura where it precedes migraine pain but does not damage tissue. During stroke and head trauma, however, SD can arise repeatedly near the site of injury and may promote neuronal damage. We developed a superfused brain slice preparation that can repeatedly support robust SD during imaging and electrophysiological recording to test drugs that may block SD. Submerged rat neocortical slices were briefly exposed to artificial cerebrospinal fluid (ACSF) with KCl elevated to 26 mM. SD was evoked within 2 min, recorded in layers II/III both as a negative DC shift and as a propagating front of elevated light transmittance (LT) representing transient cell swelling in all cortical layers. An SD episode was initiated focally and could be repeatedly evoked and imaged with no damage to slices. As reported in vivo, pretreatment with one of several N-methyl-d-aspartate (NMDA) receptor antagonists blocked SD, but a non-NMDA glutamate receptor antagonist (CNQX) had no effect. NMDA receptor (NMDAR) activation does not initiate SD nor are NMDAR antagonists tolerated therapeutically so we searched for more efficacious drugs to block SD generation. Pretreatment with the sigma-one receptor (ς1R) agonists dextromethorphan (10–100 μM), carbetapentane (100 μM), or 4-IBP (30 μM) blocked SD, even when KCl exposure was extended beyond 5 min. The block was independent of NMDA receptor antagonism. Two ς1R antagonists [(+)-3PPP and BD-1063] removed this block but had no effect upon SD alone. Remarkably, the ς1R agonists also substantially reduced general cell swelling evoked by bath application of 26 mM KCl. More potent ς1R ligands that are therapeutically tolerated could prove useful in reducing SD associated with migraine and be of potential use in stroke or head trauma.
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Franco, Rafael, Rafael Rivas-Santisteban, Mireia Casanovas, Alejandro Lillo, Carlos A. Saura, and Gemma Navarro. "Adenosine A2A Receptor Antagonists Affects NMDA Glutamate Receptor Function. Potential to Address Neurodegeneration in Alzheimer’s Disease." Cells 9, no. 5 (April 26, 2020): 1075. http://dx.doi.org/10.3390/cells9051075.
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(1) Background. N-methyl d-aspartate (NMDA) ionotropic glutamate receptor (NMDAR), which is one of the main targets to combat Alzheimer’s disease (AD), is expressed in both neurons and glial cells. The aim of this paper was to assess whether the adenosine A2A receptor (A2AR), which is a target in neurodegeneration, may affect NMDAR functionality. (2) Methods. Immuno-histo/cytochemical, biophysical, biochemical and signaling assays were performed in a heterologous cell expression system and in primary cultures of neurons and microglia (resting and activated) from control and the APPSw,Ind transgenic mice. (3) Results. On the one hand, NMDA and A2A receptors were able to physically interact forming complexes, mainly in microglia. Furthermore, the amount of complexes was markedly enhanced in activated microglia. On the other hand, the interaction resulted in a novel functional entity that displayed a cross-antagonism, that could be useful to prevent the exacerbation of NMDAR function by using A2AR antagonists. Interestingly, the amount of complexes was markedly higher in the hippocampal cells from the APPSw,Ind than from the control mice. In neurons, the number of complexes was lesser, probably due to NMDAR not interacting with the A2AR. However, the activation of the A2AR receptors resulted in higher NMDAR functionality in neurons, probably by indirect mechanisms. (4) Conclusions. A2AR antagonists such as istradefylline, which is already approved for Parkinson’s disease (Nouriast® in Japan and Nourianz® in the US), have potential to afford neuroprotection in AD in a synergistic-like fashion. i.e., via both neurons and microglia.
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Sang, Christine N. "NMDA-Receptor Antagonists in Neuropathic Pain." Journal of Pain and Symptom Management 19, no. 1 (January 2000): 21–25. http://dx.doi.org/10.1016/s0885-3924(99)00125-6.
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Muir, William W. "NMDA Receptor Antagonists and Pain: Ketamine." Veterinary Clinics of North America: Equine Practice 26, no. 3 (December 2010): 565–78. http://dx.doi.org/10.1016/j.cveq.2010.07.009.
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DICKENSON, A. H. "NMDA receptor antagonists: interactions with opioids." Acta Anaesthesiologica Scandinavica 41, no. 1 (January 1997): 112–15. http://dx.doi.org/10.1111/j.1399-6576.1997.tb04624.x.
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McCauley, John A. "Amide-containing NR2B/NMDA receptor antagonists." Expert Opinion on Therapeutic Patents 16, no. 6 (May 24, 2006): 863–70. http://dx.doi.org/10.1517/13543776.16.6.863.
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KOEK, W., M. S. KLEVEN, and F. C. COLPAERT. "BEHAVIOURAL PHARMACOLOGY OF NMDA RECEPTOR ANTAGONISTS." Behavioural Pharmacology 6, no. 5 (August 1995): 622. http://dx.doi.org/10.1097/00008877-199508000-00047.
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Maj, J. "NMDA receptor antagonists and antidepressant drugs." Pharmacological Research 25 (May 1992): i. http://dx.doi.org/10.1016/1043-6618(92)90253-8.
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Campos, Carlos A., Jason S. Wright, Krzysztof Czaja, and Robert C. Ritter. "CCK-Induced Reduction of Food Intake and Hindbrain MAPK Signaling Are Mediated by NMDA Receptor Activation." Endocrinology 153, no. 6 (April 16, 2012): 2633–46. http://dx.doi.org/10.1210/en.2012-1025.
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The dorsal vagal complex of the hindbrain, including the nucleus of the solitary tract (NTS), receives neural and humoral afferents that contribute to the process of satiation. The gut peptide, cholecystokinin (CCK), promotes satiation by activating gastrointestinal vagal afferents that synapse in the NTS. Previously, we demonstrated that hindbrain administration of N-methyl-d-aspartate (NMDA)-type glutamate receptor antagonists attenuate reduction of food intake after ip CCK-8 injection, indicating that these receptors play a necessary role in control of food intake by CCK. However, the signaling pathways through which hindbrain NMDA receptors contribute to CCK-induced reduction of food intake have not been investigated. Here we report CCK increases phospho-ERK1/2 in NTS neurons and in identified vagal afferent endings in the NTS. CCK-evoked phospho-ERK1/2 in the NTS was attenuated in rats pretreated with capsaicin and was abolished by systemic injection of a CCK1 receptor antagonist, indicating that phosphorylation of ERK1/2 occurs in and is mediated by gastrointestinal vagal afferents. Fourth ventricle injection of a competitive NMDA receptor antagonist, prevented CCK-induced phosphorylation of ERK1/2 in hindbrain neurons and in vagal afferent endings, as did direct inhibition of MAPK kinase. Finally, fourth ventricle administration of either a MAPK kinase inhibitor or NMDA receptor antagonist prevented the reduction of food intake by CCK. We conclude that activation of NMDA receptors in the hindbrain is necessary for CCK-induced ERK1/2 phosphorylation in the NTS and consequent reduction of food intake.
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Holsträter, Thorsten Frederik, Michael Georgieff, Karl Josef Föhr, Werner Klingler, Miriam Elisabeth Uhl, Tobias Walker, Sarah Köster, Georg Grön, and Oliver Adolph. "Intranasal Application of Xenon Reduces Opioid Requirement and Postoperative Pain in Patients Undergoing Major Abdominal Surgery." Anesthesiology 115, no. 2 (August 1, 2011): 398–407. http://dx.doi.org/10.1097/aln.0b013e318225cee5.
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Background Both central sensitization after peripheral tissue injury and the development of opioid tolerance involve activation of N-methyl-D-aspartate (NMDA) receptors. At subanesthetic doses the NMDA receptor antagonist xenon suppresses pain-evoked sensitization of pain-processing areas in the central nervous system. Although numerous studies describe the effect of NMDA receptor antagonists on postoperative pain, clinical studies elucidating their intraoperative analgesic potency when applied in a low dosage are still largely missing. Methods To analyze the analgesic effect of low-dose xenon using new application methods, the authors tested nasally applied xenon as an add-on treatment for analgesia in 40 patients undergoing abdominal hysterectomy. Within a randomized double-blind placebo-controlled study design, intraoperative and postoperative requirement of opioids as well as postoperative subjective experiences of pain were measured as primary outcome variables. Results Intranasal application of xenon significantly reduced intraoperative opioid requirement (mean difference [MD] -2.0 μg/min; 95% CI [CI95]-0.53 to -3.51, Bonferroni correction adjusted P value [pcorr]= 0.028) without relevant side effects and significantly reduced postoperative pain (MD -1.34 points on an 11-point rating scale; CI95 -0.60 to -2.09, pcorr = 0.002). However, postoperative morphine consumption (MD -8.8 μg/min; CI95 1.2 to -18.8, pcorr = 0.24) was not significantly reduced in this study. Conclusions Low-dose xenon significantly reduces intraoperative analgesic use and postoperative pain perception. Because NMDA receptor antagonists suppress central sensitization, prevent the development of opioid tolerance, and reduce postoperative pain, the intraoperative usage of NMDA receptor antagonists such as xenon is suggested to improve effectiveness of pain management within a concept of multimodal analgesia.
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FISCHER, ANDY J., RUTH L. P. SELTNER, and WILLIAM K. STELL. "Opiate and N-methyl-D-aspartate receptors in form-deprivation myopia." Visual Neuroscience 15, no. 6 (November 1998): 1089–96. http://dx.doi.org/10.1017/s0952523898156080.
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Pharmacological studies have implicated retinal opiate pathways in the visual regulation of ocular growth. However, the effects of opiate receptor subtype-specific compounds on form-deprivation myopia (FDM) are inconsistent (Seltner et al., 1997), and may be mediated by non-opiate receptors. The purpose of this study was to test whether opiate receptor-inactive (D-) enantiomers elicit the same FDM-suppressing effect as their opiate receptor-active (L-) counterparts. Since some opiates are thought to act at NMDA receptors, we also tested whether NMDA receptor agonists and antagonists influence ocular growth or FDM. We found that both L- and D- enantiomers of morphine-like compounds (dextrorphanol and levorphanol, and D- and L-naloxone) were equally effective in blocking FDM. The NMDA receptor antagonists dextromethorphan, MK801, and AP5 also suppressed FDM. A single toxic dose of NMDA, that destroys many subtypes of amacrine cells (including those that synthesize the opioid peptide enkephalin), induced myopia and ocular enlargement in ungoggled eyes, and eliminated the ability of form-deprivation to enhance ocular growth. The NR-1 subunit of the NMDA receptor was localized to a narrowly stratified, intense stratum at approximately 50% depth in the inner plexiform layer, diffusely throughout the proximal inner plexiform layer, and to many somata in the amacrine and ganglion cell layers. These observations suggest that most effects of opiate receptor ligands on FDM in the chick are mediated by non-opiate receptors, which are likely to include NMDA receptors. NMDA as an excitotoxin transiently enhances ocular growth, but thereafter disables retinal mechanisms that promote emmetropization and FDM. These observations are consistent with a prominent role for pathways utilizing NMDA receptors in FDM and ocular growth-control.
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Hellier, Jennifer L., David R. Grosshans, Steven J. Coultrap, Jethro P. Jones, Peter Dobelis, Michael D. Browning, and Kevin J. Staley. "NMDA Receptor Trafficking at Recurrent Synapses Stabilizes the State of the CA3 Network." Journal of Neurophysiology 98, no. 5 (November 2007): 2818–26. http://dx.doi.org/10.1152/jn.00346.2007.
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Metaplasticity describes the stabilization of synaptic strength such that strong synapses are likely to remain strong while weak synapses are likely to remain weak. A potential mechanism for metaplasticity is a correlated change in both N-methyl-d-aspartate (NMDA) receptor-mediated postsynaptic conductance and synaptic strength. Synchronous activation of CA3–CA3 synapses during spontaneous bursts of population activity caused long-term potentiation (LTP) of recurrent CA3–CA3 glutamatergic synapses under control conditions and depotentiation when NMDA receptors were partially blocked by competitive antagonists. LTP was associated with a significant increase in membrane-bound NMDA receptors, whereas depotentiation was associated with a significant decrease in membrane-bound NMDA receptors. During burst activity, further depotentiation could be induced by sequential reductions in antagonist concentration, consistent with a depotentiation-associated reduction in membrane-bound NMDA receptors. The decrease in number of membrane-bound NMDA receptors associated with depotentiation reduced the probability of subsequent potentiation of weakened synapses in the face of ongoing synchronous network activity. This molecular mechanism stabilizes synaptic strength, which in turn stabilizes the state of the CA3 neuronal network, reflected in the frequency of spontaneous population bursts.
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Jang, Jun Ho, Taick Sang Nam, Jaebeom Jun, Se Jung Jung, Dong-Wook Kim, and Joong Woo Leem. "Peripheral NMDA Receptors Mediate Antidromic Nerve Stimulation-Induced Tactile Hypersensitivity in the Rat." Mediators of Inflammation 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/793624.
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We investigated the role of peripheral NMDA receptors (NMDARs) in antidromic nerve stimulation-induced tactile hypersensitivity outside the skin area innervated by stimulated nerve. Tetanic electrical stimulation (ES) of the decentralized L5 spinal nerve, which induced enlargement of plasma extravasation, resulted in tactile hypersensitivity in the L4 plantar dermatome of the hind-paw. When intraplantar (i.pl.) injection was administered into the L4 dermatome before ES, NMDAR and group-I metabotropic Glu receptor (mGluR) antagonists and group-II mGluR agonist but not AMPA/kainate receptor antagonist prevented ES-induced hypersensitivity. I.pl. injection of PKA or PKC inhibitors also prevented ES-induced hypersensitivity. When the same injections were administered after establishment of ES-induced hypersensitivity, hypersensitivity was partially reduced by NMDAR antagonist only. In naïve animals, i.pl. Glu injection into the L4 dermatome induced tactile hypersensitivity, which was blocked by NMDAR antagonist and PKA and PKC inhibitors. These results suggest that the peripheral release of Glu, induced by antidromic nerve stimulation, leads to the expansion of tactile hypersensitive skin probably via nociceptor sensitization spread due to the diffusion of Glu into the skin near the release site. In addition, intracellular PKA- and PKC-dependent mechanisms mediated mainly by NMDAR activation are involved in Glu-induced nociceptor sensitization and subsequent hypersensitivity.
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Mayer, M. L., G. L. Westbrook, and L. Vyklicky. "Sites of antagonist action on N-methyl-D-aspartic acid receptors studied using fluctuation analysis and a rapid perfusion technique." Journal of Neurophysiology 60, no. 2 (August 1, 1988): 645–63. http://dx.doi.org/10.1152/jn.1988.60.2.645.
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1. Mouse hippocampal neurons in dissociated culture were grown at low density on previously plated hippocampal glial cell cultures and voltage clamped using the tight seal whole-cell patch-clamp technique. Flow pipes were used to rapidly exchange the extracellular solution, and to apply N-methyl-D-aspartic acid (NMDA) and some NMDA antagonists. Fluctuation analysis was used to estimate changes in the behavior of NMDA-activated ion channels during application of antagonists. In the presence of NMDA control spectra were well fit by single Lorentzian functions consistent with mean open times of 5-6 ms. 2. Two antagonists thought to act at the NMDA receptor agonist recognition site, 2-amino-5-phosphonovaleric acid (AP5) and kynurenic acid, did not produce changes in the mean open time or single channel conductance, consistent with their action as competitive antagonists. Onset of antagonism and recovery from the action of both AP5 and kynurenic acid was rapid and complete within 1 s. However, raising the extra-cellular glycine concentration, from 1 microM to 1 mM, reduced the potency of 100 microM kynurenic acid as an NMDA antagonist, suggesting that kynurenate has an additional action as a competitive antagonist at the glycine modulatory site on NMDA receptor channels. 3. In the presence of 150 microM magnesium NMDA spectra recorded at -60 mV were fit by double Lorentzian functions, consistent with single-channel events consisting of bursts of openings lasting 3.3 ms in duration, interrupted by blocking and unblocking events of average duration 0.18 ms. The onset and recovery from magnesium antagonism was rapid, and complete within 1 s, but was highly voltage dependent and at +40 mV magnesium (150 microM) failed to produce NMDA antagonism. These results are consistent with a voltage-dependent channel block of NMDA receptor channels produced by binding of magnesium to a site within the ion channel. 4. Zinc (30 microM) was a potent NMDA antagonist at both -60 and +40 mV, and at either potential appeared to reduce the mean open time of NMDA-activated ion channels from about 5 ms to approximately 3 ms. Over the frequency range measured, 1-1,000 Hz, NMDA spectra were well fit by single Lorentzians during zinc antagonism, in contrast to results obtained with magnesium. The mean single channel conductance also decreased in the presence of zinc to approximately 75% of control. Onset of antagonism and recovery from the action of zinc was rapid and complete within 1 s.(ABSTRACT TRUNCATED AT 400 WORDS)
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Mueller, Patrick J., C. Michael Foley, Helen W. Vogl, Meredith Hay, and Eileen M. Hasser. "Cardiovascular response to a group III mGluR agonist in NTS requires NMDA receptors." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 289, no. 1 (July 2005): R198—R208. http://dx.doi.org/10.1152/ajpregu.00185.2004.
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Previous studies have demonstrated that microinjection of the putative group III metabotropic glutamate receptor (mGluR) agonist, l(+)-2-amino-4-phosphonobutyric acid (l-AP4), into the nucleus tractus solitarius (NTS) produces depressor and sympathoinhibitory responses. These responses are significantly attenuated by a group III mGluR antagonist and may involve ionotropic glutamatergic transmission. Alternatively, a previous report in vitro suggests that preparations of l-AP4 may nonspecifically activate NMDA channels due to glycine contamination (Contractor A, Gereau RW, Green T, and Heinemann SF. Proc Natl Acad Sci USA 95: 8969–8974, 1998). Therefore, the present study tested whether responses to l-AP4 specifically require the N-methyl-d-aspartate (NMDA) receptor and whether they are due to actions at the glycine site on the NMDA channel. To test these possibilities in vivo, we performed unilateral microinjections of l-AP4, glycine, and selective antagonists into the NTS of urethane-anesthetized rats. l-AP4 (10 mM, 30 nl) produced sympathoinhibitory responses that were abolished by the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (AP-5, 10 mM) but were unaffected by the non-NMDA antagonist 6-nitro-7-sulfamobenzoquinoxaline-2,3-dione (NBQX, 2 mM). Microinjection of glycine (0.02–20 mM) failed to mimic sympathoinhibitory responses to l-AP4, even in the presence of the inhibitory glycine antagonist, strychnine (3 mM). Strychnine blocked pressor and sympathoexcitatory actions of glycine (20 mM) but failed to reveal a sympathoinhibitory component due to presumed activation of NMDA receptors. The results of these experiments suggest that responses to l-AP4 require NMDA receptors and are independent of non-NMDA receptors. Furthermore, although it is possible that glycine contamination or other nonspecific actions are responsible for the sympathoinhibitory actions of l-AP4, our data and data in the literature argue against this possibility. Thus we conclude that responses to l-AP4 in the NTS are mediated by an interaction between group III mGluRs and NMDA receptors. Finally, we also caution that nonselective actions of l-AP4 should be considered in future studies.