N-Methyl-D-Aspartate (NMDA) Receptors
The NMDA receptor belongs to the ionotropic glutamate receptor family and is responsible for mediating excitatory neurotransmission in the central nervous system. It is a heterotetramer, made up of two glycine-binding GluN1 subunits with 8 splice variants and two glutamate-binding GluN2 subunits with 4 subtypes (2A to D), which render the receptor with different expression patterns in the brain. This ligand-gated ion channel is permeable to Ca2+, Na+ and K+ ions and has a voltage dependent Mg2+ block.
The NMDA receptor is critical for nearly every function of the brain and is involved in learning, memory, brain development and synaptic plasticity. NMDA receptor dysfunction has been implicated in numerous neurological disorders, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, schizophrenia and depression.
In Vivo characterization of NMDA Modulators for Analgesic Tolerance
Drug overdose is the leading cause of accidental death in US, with 60% of cases due to chronic opioid use.
Analgesic Tolerance refers to a decreased response to analgesic effects of opioids, requiring higher doses to achieve desired effect. The over-activation of NMDARs has been implicated in development of tolerance.
Our research in this field aim to answer the following:
- Can our novel NMDAR modulators elicit analgesia on their own?
- What effect do they have on development of analgesic tolerance?
- What is the effect of pH boost?
- Can our modulators potentiate the anti-nociceptive effects of morphine (leftward shift in morphine dose-response curve with addition of compound)?
- Can our modulators reverse tolerance once it has been established?
- Do they adversely affect learning and/or memory?