The role of ionotropic glutamate receptors in chronic central pain after spinal cord injury



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Spinal cord injury (SCI) results in both loss of function and chronic central pain syndromes. In the clinical population, pain is characterized based on anatomical location: 1) Below-level pain – located at dermatomes corresponding to spinal segments caudal to the injury site, 2) At-level pain – located at dermatomes corresponding to spinal segments immediately adjacent to the injury site, 3) Above-level pain – located at segments rostral to the injury site (in area of sensory preservation). \r\n A contusion model of SCI was first characterized behaviorally and electrophysiologically. A contusion at spinal segment T10 at 150 kdynes of force and a 1 second dwell time resulted in the pain like behavior in the hindlimbs, thoracic region, and forelimbs 35 days post-injury. These contused animals exhibited spinal hyperexcitability during extracellular single-unit electrophysiological spinal recordings from the dorsal horn of the lumbar enlargement (below-level), thoracic cord (at-level; immediately rostral to injury site), and brachial enlargement (above level). \r\n In models of peripheral injury, increased ionotropic glutamate receptor mediated activity results in spinal central sensitization. Extracellular single-unit recordings from all three regions of the spinal cord (lumbar enlargement, thoracic cord, and brachial enlargement) were made on both contused and non-contused animals during ionotropic glutamate antagonist treatment (D-AP5 or NBQX). The thoracic cord, which is nearest to the site of injury, showed the greatest increase in ionotropic glutamate receptor mediated activity. \r\n Calcium-calmodulin protein kinase II (CaMKII) has been shown to be responsible for enhancing ionotropic glutamate receptor mediated activity. CaMKII also has been shown to be a molecular intermediate in both long-term potentiation (LTP) and peripherally induced central sensitization. After contusive SCI, the segments immediately rostral to the injury site show an increase in activated CaMKII. Application of CaMKII inhibitor, KN-93, during recording 35 days post injury, reduces spinal hyperexcitability induced by SCI. \r\n