From the Guidelines
Yes, NMDA receptor antagonists do block overstimulation of glutamate receptors in extrasynaptic areas, thereby reducing excitotoxic effects in the central nervous system.
Mechanism of Action
NMDA receptor antagonists like ketamine work by binding to the NMDA receptor and preventing glutamate from activating it, as stated in a study published in the Journal of the National Comprehensive Cancer Network 1. This mechanism is particularly important in pathological conditions where excessive glutamate release leads to calcium influx through extrasynaptic NMDA receptors.
Clinical Use
Ketamine, a noncompetitive N-methyl D-aspartate receptor antagonist, has been shown to produce analgesia and modulate central sensitization, hyperalgesia, and opioid tolerance at low (subanesthetic) doses 1. Although there are limited data regarding the use of ketamine as an adjuvant to opioids for management of cancer pain, a systematic review of the evidence on ketamine for treating cancer-related pain concluded that the data, although limited, did suggest modest analgesic potential for ketamine 1.
Key Points
- NMDA receptor antagonists block glutamate receptors in extrasynaptic areas, reducing excitotoxic effects in the CNS.
- Ketamine is a noncompetitive NMDA receptor antagonist that produces analgesia and modulates central sensitization, hyperalgesia, and opioid tolerance at low doses.
- Limited data support the use of ketamine as an adjuvant to opioids for management of cancer pain, but it may have modest analgesic potential 1.
From the FDA Drug Label
Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer’s disease Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels.
Memantine, as an NMDA receptor antagonist, is believed to block overstimulation of glutamate receptors in the central nervous system (CNS), which may contribute to the symptomatology of Alzheimer's disease. However, the provided text does not explicitly state that this action occurs in the extrasynaptic area or that it causes excitatory effects. The FDA label does not explicitly answer the question about the extrasynaptic area or the causation of excitatory effects. Therefore, based on the provided information, no conclusion can be drawn about the specific effects of memantine in the extrasynaptic area or its relationship to excitatory effects in the CNS 2.
From the Research
NMDA Receptor Antagonists and Glutamate Receptors
- NMDA receptor antagonists, such as memantine and ketamine, have been shown to block excessive NMDA receptor activity without disrupting normal activity 3, 4.
- These antagonists can prevent overstimulation of glutamate receptors in the extrasynaptic area, which can lead to excitatory effects in the central nervous system (CNS) 3, 5.
- Memantine, in particular, has been found to preferentially block excessive NMDA receptor activity by entering the receptor-associated ion channel preferentially when it is excessively open 3.
- Ketamine, on the other hand, has been shown to differentially alter NMDAR desensitization and stabilize a Ca2+-dependent desensitized state 4.
Mechanisms of NMDA Receptor Antagonists
- The mechanisms of NMDA receptor antagonists, such as ketamine, involve blocking the NMDA receptor channel and preventing the influx of calcium ions into the neuron 6, 5.
- This can lead to a decrease in excitatory synaptic transmission and a reduction in depression-like behavior 6, 7.
- NMDA receptor antagonists can also increase the expression of synaptic proteins, such as AMPAR subunits, and induce long-term potentiation (LTP) in the hippocampus 7.
Therapeutic Targets for Depression Treatment
- NMDA receptors have been identified as a potential therapeutic target for the treatment of depression 5, 7.
- Ketamine and other NMDA receptor antagonists have been shown to have rapid antidepressant effects in treatment-resistant depressed patients 5, 7.
- The development of new NMDA receptor modulators that can target specific receptor states or subunits may lead to more effective treatments for depression 5, 7.