· General description
· Activation process
· Physiological role
Type |
·
Ligand-gated voltage-dependent glutamate
receptor |
Location |
· Spinal cord: especially dorsal horn 2° nociceptive afferents · Brain: especially hippocampus |
Structure |
· Transmembrane · 2 x NR1 subunits (pore-forming) · 1 x NR2A subunit (binds glutamate) · 1 x NR2B (binds glycine) |
Binding sites |
· Orthosteric site: for glutamate · Coactivating site: glycine · Phencyclidine site: ketamine, PCP · Pore: blocked by Mg2+ · N2O and Xe: site unknown (antagonists) |
1.Priming |
· Activation of adjacent AMPA or NK-1 receptors · Partial depolarisation -> removal of Mg2+ plug |
2.Coactivation |
· Binding of glycine |
3.Activation |
· Binding of glutamate · Ion flux (Ca2+ influx > Na+ influx = K+ efflux) · Cell-dependent downstream effects |
Receptor |
· Non-competitive antagonist at PCP site · ↓Receptor activation |
Cellular effect |
· ↓Ca2+-mediated cell activation · ↓2nd messenger signalling · ↓Gene transcription |
Analgesic effect |
· ↓Receptor excitability = wind-up -> ↓hyperalgaesia, allodynia · ↓Synaptic reinforcement = long-term potentiation · ↓Acute somatic and neuropathic pain · ↓Opioid requirement · ↓Progression to chronic pain · Less utility once chronic pain established |
Other use |
· Dissociative general anaesthesia, including single agent use · Poorly understood effect on cell toxicity o ↓Ca2+ mediated excitotoxicity o ↑Neuronal damage in young rodents · ? Beneficial effect in depression |
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