Excitatory Mechanisms

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The afferent barrage associated with peripheral nerve injury is associated with the development of a sustained state of hyperexcitability of dorsal horn neurons, a process dubbed central sensitization.106'107 In addition to events such as lowering of activation thresholds of spinal neurons, central sensitization is characterized by the appearance of "wind-up."108'109'110 Wind-up is characterized by an increasing response to repeated C-fiber volleys, and may contribute to hyperalgesia in humans. However, the exact relationship of the relatively shortlived phenomenon of wind-up and the persistent state of central sensitization remains to be fully elucidated.111

The excitatory amino acid glutamate is the major excitatory neurotransmitter released at the central terminals of primary afferent nociceptive neurons following noxious stimulation. Glutamate acts at a number of post-synaptic receptors, including metabotropic (mGluRs) and the ionotropic a-amino-3-hydroxyl-5-methyl-4-isoxazole (AMPA), kainate and N-methyl-D-aspartic acid (NMDA) receptors. A large body of evidence suggests that the NMDA receptor subtype is the most intimately involved in central sensitization associated with inflammation and nerve injury.110 For glutamate to exert its effects, receptor phosphorylation and the removal of an Mg21-dependent ion channel block are critical events in activating the NMDA receptor. NK1 (substance P), AMPA (glutamate), and trkB (BDNF) receptors and the activation of intracel-lular serine/threonine and tyrosine kinase signalling cascades are all involved in this permissive process.112,113

NMDA receptors are also involved in the maintenance of central sensitization. Nerve injury induces increased release of excitatory amino acids into the spinal dorsal horn which is associated, in an NMDA receptor-dependent manner, with increased intracellular calcium concentration ([Ca21]i) in dorsal horn neurons.114 Initial NMDA receptor activation contributes to further increased concentrations of glutamate and aspartate, representing a continual positive feedback loop which maintains sensitization. The increased [Ca21] could also form a positive feedback loop, potentially through indirect activation of protein kinase C (PKC), a hypothesis supported by the antihypersensitivity effect of a PKC inhibitor in the SNL model of neuropathic pain,115 as well as the evidence that deletion of genes for isoforms of adenylate cyclase, protein kinase A, and protein kinase C all impair the development of pain hypersensitivity in transgenic mice

116, 117

Activity-dependent central sensi-

tization is displayed by many cells in both the superficial and deep laminae of the dorsal horn. However, in the context of pain hypersensitivity, the effect of sensitization appears to be particularly important for lamina I spi-nothalamic or spinoparabrachial projection neurons, particularly those expressing the NK1 receptor.118,119

In addition to Ca21 influx through the NMDA ion channel inducing heterosynaptic potentiation in dorsal horn neurons, activation of voltage-gated calcium channels can enhance excitatory transmission through NMDA receptor-independent mechanisms.120 For example, neu-rotrophins such as BDNF, acting through their cognate Trk receptors, facilitate synaptic transmission,121,122 partly through a NMDA receptor independent mechanism. Synaptic transmission may also be enhanced by cytokines, such as TNFa, which may be released from glial cells in the dorsal horn.123 Pharmacological studies support a role for NMDA receptors in neuropathic pain.

Pre- and postinjury intraperitoneal administration of the NMDA receptor antagonist MK-801 prevented hyper-sensitivity in the CCI model124 and electrophysiological data also demonstrates that MK-801 significantly reduces the hyperresponsiveness to noxious stimulation after peripheral nerve injury.125

The agonist action of glutamate at the NMDA receptor can be modulated by glycine.126 Antagonizing the glycine modulatory site of the NMDA receptor prevents development of hypersensitivity following peripheral nerve injury and attenuates wind-up in isolated spinal cord neurons.127 Coadministration of a glycine/NMDA receptor antagonist and morphine has also been demonstrated to attenuate pain behavior in an animal model of trigeminal neuralgia.128

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