Cellular Neuroplasticity Mechanisms Mediating Pain Persistence

Transmission of noxious-stimulus-evoked inputs in the spinal and trigeminal systems is mediated primarily through excitatory gluta-matergic synapses using alpha amino-3-hydroxy-5-methyl-4-isoxa-zole-propionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) subtypes of glutamate receptors. Glutamatergic synapses exhibit multiple forms of short-lasting and long-lasting synaptic plasticity. Persistent enhancement of nociceptive transmission, known as “central sensitization,” is a form of lasting plasticity that is similar mechanistically to long-term potentiation of glutamater-gic transmission in other regions of the central nervous system. This potentiation of AMPA/kainate transmission is dependent upon the activity of NMDA receptors, which become enhanced following noxious peripheral stimulation as a result of several con-vergent mechanisms. Central sensitization is thus an expression of increased synaptic gain at glutamatergic synapses in central noci-ceptive-transmission neurons and thereby contributes importantly to pain hypersensitivity. In addition, recent evidence has revealed a new player in the mechanisms underlying pain hypersensitivity fol-lowing nerve injury—microglia. Understanding of the roles of microglia may lead to new strategies for the diagnosis and manage-ment of neuropathic pain.

glutamate receptors; microglia; pain; spinal dorsal horn; synaptic plasticity; tyrosine kinases

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