Antinociceptive action of GLYX-13: an N-methyl-D-aspartate receptor glycine site partial agonist

@article{Wood2008AntinociceptiveAO,
  title={Antinociceptive action of GLYX-13: an N-methyl-D-aspartate receptor glycine site partial agonist},
  author={Paul L Wood and Siddique A. Mahmood and Joseph r. Moskal},
  journal={NeuroReport},
  year={2008},
  volume={19},
  pages={1059-1061}
}
Inhibition of N-methyl-D-aspartate (NMDA)-mediated neurotransmission has been demonstrated to provide antinociceptive actions in a number of animal models of tonic and neuropathic pain. However, both competitive and noncompetitive NMDA receptor antagonists are ataxic at analgesic doses. Partial agonists and antagonists of the NMDA-associated glycine site have demonstrated antinociceptive actions at doses that are not ataxic. In this study, we present data showing that GLYX-13, an NMDA receptor… 
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References

SHOWING 1-10 OF 18 REFERENCES
The antiepileptic agent gabapentin (Neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed byd-serine
TLDR
Gabapentin may represent a novel type of anxiolytic and analgesic agent that has negligible affinity for the strychnine insensitive [3H]glycine binding site and may not involve the NMDA receptor complex.
Brain but Not Spinal NR2B Receptor Is Responsible for the Anti-Allodynic Effect of an NR2B Subunit-Selective Antagonist CP-101,606 in a Rat Chronic Constriction Injury Model
TLDR
The findings suggest that the anti-allodynia effect of CP-101,606 is ascribable to blockade of NR2B receptors at the brain, but not at the spinal cord, and intrathecal injection of a non-selective NMDA antagonist, memantine, significantly inhibited CCI-induced mechanical allodynia at a dose of 300 nmol.
Effects of the N-Methyl-d-aspartate Receptor Antagonist Perzinfotel [EAA-090; [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic Acid] on Chemically Induced Thermal Hypersensitivity
TLDR
It is demonstrated that perzinfotel has therapeutic ratios for effectiveness versus adverse effects superior to those seen with other competitive and uncompetitive NMDA receptor antagonists studied.
The NMDA-receptor antagonist CPP abolishes neurogenic ‘wind-up pain’ after intrathecal administration in humans
TLDR
Early experiences with i.t. administration of NMDA-receptor antagonists to humans indicate that the NMDA -receptor system plays an important role in neurogenic pain and that antagonizing this system may be a useful way to obtain better pain control although psychotomimetic side effects due to rostral spread might be a problem.
GLYX-13: A monoclonal antibody-derived peptide that acts as an N-methyl-d-aspartate receptor modulator
TLDR
It is reported that GLYX-13, a tetrapeptide (TPPT-amide), was found to readily cross the blood-brain barrier and modulate the NMDA receptor in a glycine-like fashion when examined pharmacologically and electrophysiologically and is a new drug candidate with potential for the treatment of cognitive disorders.
Glutamate in CNS disorders as a target for drug development: an update.
The authors provide an extensive review of new data related to the role of glutamate in CNS disorders, describing new aspects in glutamate and glutamatergic receptors-NMDA receptors, NR2B-selective
Pharmacological disruption of calcium channel trafficking by the α2δ ligand gabapentin
TLDR
Evidence indicates that GBP may act chronically by displacing an endogenous ligand that is normally a positive modulator of α2δ subunit function, thereby impairing the trafficking function of the α2 δ subunits to which it binds.
L‐687,414, a low efficacy NMDA receptor glycine site partial agonist in vitro, does not prevent hippocampal LTP in vivo at plasma levels known to be neuroprotective
TLDR
A low level of intrinsic activity at the glycine site may be sufficient to support NMDA receptor‐dependent LTP but in circumstances where there is likely to be an excessiveNMDA receptor activation the agonism associated with a low efficacy partial agonist, such as L‐687,414, is dominated by the antagonist properties.
Concentration–effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain
TLDR
The reduction of the hyperalgesic area and evoked pain scores with the alfentanil infusion suggests that opioids may have some peripheral effects in the post‐nerve injury patients, and clinical utilization of opioids with careful titration may be beneficial in post‐NERV injury patients with partial deafferentation.
The effect of intrathecal gabapentin on pain behavior and hemodynamics on the formalin test in the rat.
TLDR
The results indicate that the spinal effect of gabapentin reduces the somatosympathetic reflex and somatosensory response to tissue injury without an accompanying effect on acute nociception or resting sympathetic outflow.
...
1
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