Over the past decade, there have been major advances in our understanding of the role of
glutamate and
N-methyl-d-aspartate (
NMDA) receptors in several disorders of the central nervous system, including
stroke,
Parkinson's disease,
Huntington's disease and chronic/
neuropathic pain. In particular, NR2B subunit-containing
NMDA receptors have been the focus of intense study from both a physiological and a pharmacological perspective, with several
pharmaceutical companies developing NR2B subtype-selective antagonists for several
glutamate-mediated diseases. Recent studies have shown the importance of NR2B subunits for
NMDA receptor localization and endocytosis, and have suggested a role for NR2B-containing
NMDA receptors in the underlying pathophysiology of
neurodegenerative disorders such as Alzheimer's and Huntington's diseases. Anatomical, biochemical and pharmacological studies over the past five years have greatly added to our understanding of the role of NR2B subunit-containing
NMDA receptors in chronic and
neuropathic pain states, and have shown that NR2B-mediated
analgesic effects might be supra- rather than intra-spinally mediated, and that phosphorylation of the NR2B subunit could be responsible for the initiation and maintenance of the central sensitization seen in
neuropathic pain states. These data will hopefully provide the impetus for development of novel compounds that use multiple approaches to modulate the activity of NR2B subunit-containing
NMDA receptors, thus bringing to fruition the promise of therapeutic efficacy utilizing this approach.