NMDA RECEPTOR STRUCTURE AND FUNCTION
The synapse between the primary afferent and secondary afferent neurons in the dorsal horn of the spinal cord is a critical site for the modulation of ascending pain pathways. Glutamate is the primary excitatory amino acid (EAA) involved in excitation of the secondary afferent neuron and is primarily stored in the presynaptic vesicles of the primary afferent neuron. Upon membrane depolarization, glutamate is released and targets postsynaptic receptors, which can be either metabotropic or ionotropic. Ionotropic glutamate receptors are ligand-gated channels that regulate ion conductance of calcium and sodium. There are three major subclasses of ionotropic receptors: a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA). The discovery of several pharmacologic agents, beginning with compound (+) MK-801, that are highly selective antagonists for specific subtypes of glutamate receptors has helped clarify the characteristics and functions of the various glutamate receptors and in particular the role of the NMDA calcium channel in the central nervous system (CNS).1
Among various locations in the CNS, NMDA receptors are found on the postsynaptic terminal of second-order afferent neurons in the dorsal horn of the spinal cord that are involved in the transmission of pain signals. With the cloning of individual NMDA receptor subunit DNA sequences, it was ultimately discovered that NMDA receptors consist of glycine-binding GluN1 subunit and glutamate-binding GluN2 subunits. NMDA receptors are calcium ion channels composed of four individual subunits, including two GluN1 subunits and two GluN2 subunits, and the receptor requires coactivation by two ligands, glutamate and glycine. There is considerable diversity among receptor subtypes, which imparts distinct functional and pharmacologic properties to the NMDA receptor.1 A unique property of the NMDA receptor is that in addition to being ligand activated, its activation is also voltage dependent, that is, dependent on the resting cell potential. At a normal resting membrane state, the NMDA calcium channel is blocked by magnesium and is in an inactive state. When the resting membrane potential of the afferent neuron is changed as a result of prolonged stimulus, the channel loses the magnesium ion block, and calcium moves into the cell, raising the membrane potential, resulting in neuronal hyperexcitability.2
Sound in vivo evidence indicates that peripheral tissue or nerve injury causes not only an increase in the sensitivity of primary afferent nociceptors at the site of tissue injury but also leads to NMDA receptor–mediated central changes in synaptic excitability and, consequently, on a clinical level, a reduction in opioid responsiveness, hyperalgesia, and allodynia.3,4
WINDUP AND CENTRAL SENSITIZATION
The NMDA receptor is a key component in the modulation of the strength of synaptic pathways, a property referred to as synaptic plasticity. This is demonstrated in its involvement in the states of windup and central sensitization. Windup refers to reversible synaptic changes that can result in neuronal hyperexcitability in response to a progressive or sustained noxious ...