Postinjury Pain Hypersensitivity and NMDA Receptor Antagonists

2018 ◽  
pp. 189-192
Keyword(s):  
Pain Management ◽  
Nmda Receptor ◽  
Central Sensitization ◽  
Receptor Activation ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Primary Afferent ◽  
Pain Hypersensitivity ◽  
Pain Pathways ◽  
Nmda Receptor Activation

This case focuses on pain hypersensitivity by asking the question: Are primary afferent-induced hypersensitivity states dependent on the activation of N-methyl-d-aspartate (NMDA) receptors, and is windup (perceived increase in pain intensity with a repeatedly delivered stimulus) a possible trigger for the production of central hypersensitivity? This study demonstrated that the induction and maintenance of central sensitization are dependent on NMDA receptor activation. NMDA receptor antagonists have been shown to prevent the manifestation of central sensitization as well as to decrease established hyperactivity in pain pathways. NMDA receptor antagonists play an important role in pain management.

NMDA Receptor Antagonists, Gabapentinoids, Alpha-2 Agonists, and Dexamethasone

2018 ◽  
Author(s):  
Alexander J. Feng ◽  
George C. Chang Chien ◽  
Alan D. Kaye
Keyword(s):  
Pain Management ◽  
Nmda Receptor ◽  
Side Effect ◽  
Synergistic Effects ◽  
Adverse Outcomes ◽  
Medical Complications ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Management Options ◽  
Surgical Pain

Surgical pain is a major obstacle in the recovery of patients. Effective pain management is of upmost importance to optimize a patient’s recovery, decrease medical complications, and increase patient satisfaction. Traditional pain management with opioids and nonsteroidal anti-inflammatory drugs have significant side effect profiles leading to medical complications or insufficient pain management from reluctance of use. Adjuvant analgesic can provide improved pain management with significantly less side effect profile. In addition, the clinician can, with synergistic effects of adjuvant medications, lower the total dosages used, thus lessening the likelihood of the side effects that occur when medications are used alone at a higher dosage. This chapter presents several adjuvant analgesics—NMDA receptor antagonists, gabapentinoids, alpha-2 agonists, and dexamethasone—and evidence for their use. Ultimately, through the use of traditional pain management options along with adjuvant analgesics, the effectiveness of acute pain management can be increased while adverse outcomes are reduced and functional recovery and quality of life improved.

scholarly journals Intranasal Application of Xenon Reduces Opioid Requirement and Postoperative Pain in Patients Undergoing Major Abdominal Surgery

2011 ◽  
Vol 115 (2) ◽  
pp. 398-407 ◽  
Author(s):  
Thorsten Frederik Holsträter ◽  
Michael Georgieff ◽  
Karl Josef Föhr ◽  
Werner Klingler ◽  
Miriam Elisabeth Uhl ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Postoperative Pain ◽  
Central Sensitization ◽  
Low Dose ◽  
Rating Scale ◽  
Controlled Study ◽  
Opioid Tolerance ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Intranasal Application

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.

Use of Both Fluoro-Jade B and Hematoxylin and Eosin to Detect Cell Death in the Juvenile Rat Brain Exposed to NMDA-Receptor Antagonists or GABA-Receptor Agonists in Safety Assessment

2021 ◽  
pp. 019262332110077
Author(s):  
Catherine A. Picut ◽  
Odete R. Mendes ◽  
David S. Weil ◽  
Sarah Davis ◽  
Cynthia Swanson
Keyword(s):  
Cell Death ◽  
Nmda Receptor ◽  
Rat Brain ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Nmda Receptor Antagonists ◽  
Neonatal Rats ◽  
Receptor Antagonists ◽  
Fluoro Jade B ◽  
Hematoxylin And Eosin

Administration of pediatric anesthetics with N-methyl D-aspartate (NMDA)-receptor antagonist and/or γ-aminobutyric acid (GABA) agonist activities may result in neuronal degeneration and/or neuronal cell death in neonatal rats. Evaluating pediatric drug candidates for this potential neurotoxicity is often part of overall preclinical new drug development strategy. This specialized assessment may require dosing neonatal rats at postnatal day 7 at the peak of the brain growth spurt and evaluating brain tissue 24 to 48 hours following dosing. The need to identify methods to aid in the accurate and reproducible detection of lesions associated with this type of neurotoxic profile is paramount for meeting the changing needs of neuropathology assessment and addressing emerging challenges in the neuroscience field. We document the use of Fluoro-Jade B (FJB) staining, to be used in conjunction with standard hematoxylin and eosin staining, to detect acute neurodegeneration and neuronal cell death that can be caused by some NMDA-receptor antagonists and/or GABA agonists in the neonatal rat brain. The FJB staining is simple, specific, and sensitive and can be performed on brain specimens from the same cohort of animals utilized for standard neurotoxicity assessment, thus satisfying animal welfare recommendations with no effect on achievement of scientific and regulatory goals.

scholarly journals Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

2017 ◽  
Vol 114 (33) ◽  
pp. E6942-E6951 ◽  
Author(s):  
Genevieve E. Lind ◽  
Tung-Chung Mou ◽  
Lucia Tamborini ◽  
Martin G. Pomper ◽  
Carlo De Micheli ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Binding Affinity ◽  
Binding Mode ◽  
Structural Basis ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Glutamate Binding ◽  
Subunit Interface ◽  
The Central Nervous System ◽  
Contact Residues

NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.

d-Serine regulates CREB phosphorylation induced by NMDA receptor activation in Müller glia from the retina

2007 ◽  
Vol 427 (1) ◽  
pp. 55-60 ◽  
Author(s):  
Mónica Lamas ◽  
Irene Lee-Rivera ◽  
Mónica Ramírez ◽  
Ana María López-Colomé
Keyword(s):  
Nmda Receptor ◽  
Receptor Activation ◽  
Muller Glia ◽  
Müller Glia ◽  
Creb Phosphorylation ◽  
Nmda Receptor Activation
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