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The Neurobiology of Central Sensitization
Published in Robert M. Bennett, The Clinical Neurobiology of Fibromyalgia and Myofascial Pain, 2020
From these properties it is logical to propose that the lasting enhancement of excitatory synaptic responses at primary afferent-second order synapses in pain pathways shares a common signalling cascade with so-called NMDA receptor-dependent form of long-term potentiation [LTP] of excitatory synaptic transmission that is observed in many regions of the CNS. The mechanisms of NMDA receptor-dependent LTP have been examined in most detail for Schaffer collateral synapses onto CA1 neurons in the hippocampus, where a core signalling cascade for initiating LTP has been proposed (8,9). This requires Ca2+ influx through NMDA receptors during the tetanic stimulation which is accomplished by temporal summation of EPSPs, diminishing the Mg2+ blockade of the channel. Enhancement of NMDA channel function by the tyrosine kinase Src is also necessary and a coincident rise in postsynaptic sodium concentration may additionally contribute to boosting NMDA receptor activity (9). The resultant influx of Ca2+ sets off a cascade leading to activation of Ca2+/calmodulin dependent kinase II [CAMKII] and phosphorylation of the AMPA receptor subunit protein [GluRl] which causes AMPA channels to move to a high conductance state. Phosphorylation of AMPA receptors may also cause increased cell surface expression of AMPA receptors and allows conversion of “silent synapses,” those lacking AMPA receptors, into active ones.
Pharmacological Modification of a Cerebroplegia Solution
Published in Richard A. Jonas, Jane W. Newburger, Joseph J. Volpe, John W. Kirklin, Brain Injury and Pediatric Cardiac Surgery, 2019
Richard A. Jonas, Aoki Mitsuru
NBQX is a non-NMDA, or AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole) receptor antagonist. AMPA receptor activation results in depolarization of the cell membrane and an increase in sodium and potassium flux, and it can produce excitotoxic neuronal injury in the immature brain. In studies using mature rodents, NBQX has been demonstrated to reduce ischemic neuronal injury.10 However these studies were performed at normothermia and did not include the added insults of cardiopulmonary bypass, anticoagulation, and hemodilution.
Glutathione and Glutathione Derivatives: Possible Modulators of Ionotropic Glutamate Receptors
Published in Christopher A. Shaw, Glutathione in the Nervous System, 2018
Réka Janáky, Vince Varga, Zsolt Jenei, Pirjo Saransaari, Simo S. Oja
The ionotropic AMPA receptors are activated by AMPA, quisqualate, and glutamate. Kainate, the most potent activator of the kainate receptors, also cross-reacts with AMPA receptors, though less effectively. The AMPA and kainate receptors are inhibited by 6,7-dinitroquinoxaline-2,3-dione (DNQX), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and sulfamoylbenzo(f)quinoxaline (NBQX) and are coupled to channels highly permeable to Na+ and K+ and much less permeable to Ca2+. An activation of these receptors increases the membrane permeability for these ions, accompanied by rapid depolarization (Récasens et al. 1992). They are thus primarily responsible for the fast excitatory glutamate transmission and neuronal-glial interaction. The colocalization of NMDA and AMPA sites (reviewed in Nicoll, Malenka, and Kauer 1990) may be of significance in the repetitive activation of NMDA receptors and in the generation of long-term potentiation (LTP). The kainate receptors may function as autoreceptors, since they are located presynaptically. Their exact physiological role is not however known (Seeburg 1993).
NBQX attenuates relapse of nicotine seeking but not nicotine and methamphetamine self-administration in rats
Published in The World Journal of Biological Psychiatry, 2021
Jana Ruda-Kucerova, Petra Amchova, Filip Siska, Yousef Tizabi
Conversely, DNQX failed in suppressing selectively drug-paired operant responses under FR1 protocol as it was ineffective at lower doses. At the highest dose, it decreased responding to food as well (Pierce et al. 1997). Based on the available evidence, it seems that the reinstatement/relapse is the procedure in which the effect of AMPA/kainate antagonists can be observed, which is corroborated by our study. It seems that stimulation of AMPA receptors in the nucleus accumbens plays a crucial role in cocaine-seeking (Schmidt and Pierce 2010), consistently with the report of AMPA agonists-induced reinstatement of drug-seeking reported in cocaine (Knackstedt and Kalivas 2009) and deep involvement of AMPA receptors in the neuroplastic changes associated with behavioural sensitisation towards a variety of drugs of abuse (Vanderschuren and Kalivas 2000).
The positive allosteric modulation of GABAA receptors mRNA in immature hippocampal rat neurons by midazolam affects receptor expression and induces apoptosis
Published in International Journal of Neuroscience, 2019
Barbara Sinner, Julia Steiner, Manuela Malsy, Bernhard M. Graf, Anika Bundscherer
In the early period of brain development, glutamatergic synaptic transmission is purely NMDA-receptor based and lacks functional AMPA receptors. NMDA receptors are characterized by a higher affinity to glutamate than AMPA receptors. During the later stages of brain maturation glutamatergic transmission is also facilitated via AMPA receptors. These are assemblies consisting of four subunits GluA1–4 [8]. AMPA receptors undergo typical subunit changes during brain maturation. Early in development many synapses contain GluA2-lacking, Ca2+-permeable AMPA receptors, which are exchanged for GluA2-containing AMPA receptors after the second postnatal week. The predominant expression of GluA1 is highly developmental restricted and in 14 days old rats AMPA receptors mainly consist of GluA2 subunits [9]. Therefore, we evaluated the effect of benzodiazepine administration on GluA1 and A2 receptor expression.
The impact of perampanel and targeting AMPA transmission on anti-seizure drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Simona Lattanzi, Pasquale Striano
The improvement in the understanding of AMPA-mediated pathways and the discovery of PER opened new avenues and frontiers in the treatment of seizures. AMPA receptors play a key role in the pathogenesis of refractory status epilepticus (SE). Indeed, the transition from self-limiting to self-sustaining seizures is characterized by the internalization of the ε – subunit of γ-aminobutyric acid (GABA) receptors, with a decreased likelihood for GABAergic drugs to bind their target, and the externalization of AMPA receptors [13]. Plasticity of AMPA receptors composition in excitatory synapses, with an over-expression of calcium-permeable GluA2-lacking AMPA receptors, also occurs. Targeting AMPA transmission may be a promising strategy to overcome refractoriness and time-dependent pharmaco-resistance to benzodiazepines in SE. In a diazepam-refractory lithium-pilocarpine-induced SE model, non-competitive AMPA antagonists, namely PER and GYKI52466, were effective to terminate seizures [14]. Different PER formulation, including the intravenous form, should be made available to test its therapeutic potential in refractory SE in clinical practice [13].