PainPharm – NMDA Antagonists

Master answer

N-Methyl D-Aspartate (NMDA) Receptor

• ligand-gated voltage dependent ion channel
• Natural ligand = glutamate
• Associated with the family of glutamate receptors (AMPA, kainite and neurokinin)

Structure:

• transmembrane receptor
• 5 subunits forming central cation ionophore
• at baseline Mg2+ plugs and inhibits central cation pore

• Location: abundant throughout brain (esp. hippocampus) and spinal cord (esp. dorsal horn) on post-synaptic membranes
• Activation: NMDA receptor contains central Mg2+ plug, which block channel at rest
  • Glycine binding + voltage stimulus are required (via activation of adjacent AMPA and neurokinin receptors) → remove Mg plug → primes NMDA receptor for activation by glutamate
  • When channel activated→ opens cation channel → ↑cation conductance (Ca2+ and Na+ in; K+ out) → excitatory postsynaptic potential

Physiological Roles of NMDA Receptors in the CNS

• Wind up phenomenon
  • Wind up = repeated stimuli of same strength cause increase in pain response
  • Proposed mechanism: C fibres synapse in lamina II of dorsal horn → repeated stimulation → glutamate release → NMDA activation → ↑response of dorsal horn neurons to excitatory neurotransmitter input àhyperalgesia and allodynia
• Long term potentiation
  • LTP = strengthening of synaptic transmission that occurs following ↑activity across that synapse
  • i.e. recurrent painful stimuli → neuroplasticity → chronic pain
  • NMDA receptor stimulation leads to various intracellular changes:
    • production of NO
    • activate second messengers (IP3, DAG, cGMP, PKC)
    • PKC → increases NMDA activity → vicious cycle
    • second messengers induce oncogenes (e.g. c-fos)
• Memory
  • NMDA receptors are highly expressed in hippocampus and throughout cortex Important roles in neuroplasticity and memory formation
• Apoptosis
  • Post cerebrovascular accident → significant NMDA activation → ↑↑Ca influx → excitotoxicity → triggers neuronal apoptosis

Pharmacology of Ketamine