Brain Advance Access originally published online on August 18, 2005
Brain 2005 128(10):2359-2371; doi:10.1093/brain/awh623
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Changes in electrophysiological properties and sodium channel Nav1.3 expression in thalamic neurons after spinal cord injury
1 Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, 2 Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT and 3 Department of Surgery, Rhode Island Hospital, Brown University School of Medicine, Providence, RI, USA
Correspondence to: Stephen G. Waxman, MD, PhD, Department of Neurology, LCI-707, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA E-mail: stephen.waxman{at}yale.edu
Spinal cord contusion injury (SCI) is known to induce pain-related behaviour, as well as hyperresponsiveness in lumbar dorsal horn nociceptive neurons associated with the aberrant expression of Nav1.3, a rapidly repriming voltage-gated sodium channel. Many of these second-order dorsal horn neurons project to third-order neurons in the ventrobasal complex of the thalamus. In this study we hypothesized that, following SCI, neurons in the thalamus undergo electrophysiological changes linked to aberrant expression of Nav1.3. Adult male Sprague-Dawley rats underwent contusion SCI at the T9 thoracic level. Four weeks post-SCI, Nav1.3 protein was upregulated within thalamic neurons in ventroposterior lateral (VPL) and ventroposterior medial nuclei, where extracellular unit recordings revealed increased spontaneous discharge, afterdischarge, hyperresponsiveness to innocuous and noxious peripheral stimuli, and expansion of peripheral receptive fields. Altered electrophysiological properties of VPL neurons persisted after interruption of ascending spinal barrage by spinal cord transection above the level of the injury. Lumbar intrathecal administration of specific antisense oligodeoxynucleotides generated against Nav1.3 caused a significant reduction in Nav1.3 expression in thalamic neurons and reversed electrophysiological alterations. These results show, for the first time, a change in sodium channel expression within neurons in the thalamus after injury to the spinal cord, and suggest that these changes contribute to altered processing of somatosensory information after SCI.
Key Words: pain; spinal cord injury; VPL; channel; sodium
Abbreviations: AS = antisense; BK = background; i.t. = intrathecal; MM = mismatch; ODNs = oligodeoxynucleotides; SCI = spinal cord injury; VPL = ventroposterior lateral; VPM = ventroposterior medial
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Received May 19, 2005. Revised July 11, 2005. Accepted July 26, 2005.
* These authors contributed equally to this work
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