Neuro–Endocrine–Immune Dysfunction in the Chronic Pain Patient
Sahar Swidan, Matthew Bennett in Advanced Therapeutics in Pain Medicine, 2020
The N-methyl-D-aspartate (NMDA) receptor has been well-implicated in the development of wind-up. The NMDA receptor is an ionotropic glutamate receptor (glutamate receptor and an ion channel). At normal resting potential, the ionophore channel is blocked by Mg2+. With the Mg2+ block in place, glutamate will not be able to open the channel. However, with repetitive stimulation by AMPA and SP, the Mg2+ block is removed. If secondary glycine or D-serine sites are also occupied, activation of the NMDA receptor by glutamate can then allow entry of Ca2+ and Na+ into the cell, and K+ out of the cell. So not only is the cell depolarized, but there are increased intracellular stores of Ca2+ as well. Wind-up has been prevented by the administration of NMDA receptor antagonists.42–44
Clinical pharmacology: other adjuvants
Pamela E Macintyre, Suellen M Walker, David J Rowbotham in Clinical Pain Management, 2008
The NMDA receptor itself is a complex, ion channelcoupled receptor that is activated in vivo by glutamate, the predominant excitatory neurotransmitter of the central nervous system.38 The importance of this receptor in the context of acute and chronic pain cannot be overstated. Following injury to peripheral tissues or nerves, nociception invariably results in NMDA receptor activation, especially in the dorsal horn of the spinal cord. It is particularly noteworthy that these dorsal horn NMDA receptors are also implicated in opioid tolerance,39 opioid-induced hyperalgesia (a paradoxical phenomenon whereby opioid-treated patients develop greater sensitivity to pain),40 and are fundamental to the processes of”wind up” and “long-term potentiation” which occur in the development of persistent and neuropathic pain states.41
Organic Chemicals
William J. Rea, Kalpana D. Patel in Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
The NMDA is a specific type of ionotropic glutamate receptor. NMDA is methyl-d-aspartate—the name of a selective agonist that binds to NMDA receptors but not to other glutamate receptors. The activation of NMDA receptors results in the opening of an ion channel that is nonselective to captions with an equilibrium potential near 0 mV. A property of the NMDA receptor is its voltage-dependent activation, which opens the nerve or vascular intracellular channel which has occurred as a result of an ion channel block by extracellular Mg2+ ions. This opening allows the flow of Na+ and small amounts of Ca2+ ions into the cell and K+ to go out of the cell to be voltage dependent.18–21 This can soon cause weakness and fatigue due to K+ loss and hypersensitivity due to the combination of Ca2+ with protein kinases A and C when being phosphorylated.
Glycine transporter-1 inhibitors: a patent review (2011–2016)
Published in Expert Opinion on Therapeutic Patents, 2018
The NMDA receptor is a ligand and voltage-gated ionotropic glutamate receptor that is widely expressed throughout the CNS and periphery. Activation of it relies on the following: (1) binding of agonist l-glutamate (2) at the orthosteric binding site of the NMDA receptor GluN2 subunit with simultaneous binding of obligatory co-agonist (1 or d-serine (3)) at the GluN1 subunit strychnine-insensitive glycine-B binding site, and (2) concurrent membrane depolarization, which is required to expel a magnesium block from the channel pore [1]. Stimulation of the NMDA receptor permits calcium influx, leading to neuronal excitation and intracellular (IL) signaling cascades that facilitate long-term potentiation (LTP), long-term depression, and synaptic plasticity [5,6].
Treatment Options for Anti-N-methyl-D-aspartate Receptor Encephalitis
Published in The Neurodiagnostic Journal, 2018
N-methyl-d-aspartate (NMDA) is an excitotoxin; it destroys nerve cells by overexciting them (Watkins 2015). This water-soluble artificial element is described as not typically found in organic issue (Masuko et al. 2008). NMDA receptors are a precise type of ionotropic glutamate receptor that controls synaptic plasticity and memory function and are ubiquitous throughout the body, primarily localized in the brain and spinal cord (Kadewaga et al. 2007; Watkins 2015). These receptors are indispensable for human interaction, judgment, and memory. Ionotropic receptors are also referred to as ligand-gated ion channels (Thompson et al. 2013). The receptors are a group of transmembrane ion channel proteins that permit ions such as Ca2+ and Na+ to cross through the membrane (Thompson et al. 2013).
Is there a role for combined use of gabapentin and pregabalin in pain control? Too good to be true?
Published in Current Medical Research and Opinion, 2018
Helen Senderovich, Geetha Jeyapragasan
The NMDA receptor complex is a ligand-gated ion channel that mediates an influx of calcium ions when activated. Nociceptive stimuli cause glutamate release from excitatory synapses. Partial depolarization of the neuron after glutamine activation will allow calcium influx into the neuron. These receptors are known to be found in high concentrations in the hippocampus, and have been attributed a key role in the process of central sensitization of painful stimuli, commonly known as the “wind-up” phenomenon leading to hyperalgesia. NMDA receptors also play an important role in pain signaling in the spinal cord dorsal horn. In fact, it was found that enhancing NMDA receptors within the dorsal horn by bradykinin activated multiple kinases which produced pain hypersensitivity7. Sutton et al. showed that, in the rat neocortex, gabapentin inhibits neuronal calcium influx in a concentration-dependent manner by inhibiting the P and Q isoforms of α1ACa2 + (P/Q-type) calcium channels21. The decreased calcium influx reduces excitatory amino acid (e.g. glutamate) release, leading to decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation, responsible for hyperalgesia. Noradrenaline release in the brain is increased, further enhancing the analgesic action through descending spinal pathways14,22.
Related Knowledge Centers
- Ampa Receptor
- Glutamate Receptor
- Glutamic Acid
- Glycine
- Ionotropic Glutamate Receptor
- Ligand
- Ion Channel
- Neuron
- Kainate Receptor
- Serine