NMDA receptors and signaling in chronic neuropathic pain

Chronic pain, especially neuropathic pain resulting from damage to the peripheral or central nervous system, is a major clinical problem that remains difficult to treat. The glutamate N-methyl-d-aspartate receptors (NMDARs) are widely distributed along the pain pathway and are critically involved in synaptic plasticity in chronic pain states. Although NMDAR antagonists, such as ketamine and memantine, have little effect on normal nociception, they are effective in treating neuropathic pain in animal models and in humans. Increased presynaptic NMDAR activity at primary afferent terminals potentiates excitatory input to spinal dorsal horn neurons, while increased postsynaptic NMDAR activity can increase neuronal excitability and diminish synaptic inhibition through promoting K⁺-Cl⁻ cotransporter-2 proteolysis. Identifying the molecular mechanisms behind this increase in NMDAR activity, including protein phosphorylation and protein-protein interactions, could facilitate the development of new drugs that specifically reverse abnormal NMDAR hyperactivity in chronic pain with minimal impairment of the physiological functions of NMDARs.