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Upregulation of persistent and ramp sodium current in dorsal horn neurons after spinal cord injury

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Abstract

Traumatic spinal cord injury (SCI) results not only in motor impairment, but also in chronic central neuropathic pain, which often is refractory to conventional treatment approaches. Upregulated expression of sodium channel Nav1.3 has been observed within the spinal dorsal horn neurons after SCI, and appears to contribute to neuronal hyperresponsiveness and pain-related behaviors. In this study we characterized the changes in sodium current properties within dorsal horn neurons after contusive SCI. Four weeks after adult male Sprague-Dawley rats underwent T9 spinal cord contusion injury, when behavioral nociceptive thresholds were decreased to both mechanical and thermal stimuli, whole-cell patch-clamp recordings were performed on acutely dissociated lumbar dorsal horn neurons. The cells demonstrated characteristic fast-activating and fast-inactivating sodium currents. SCI led to a shift of the steady-state activation and inactivation of the sodium current towards more depolarized potentials. The shifted steady-state inactivation shows similarities to that obtained from axotomized dorsal root ganglions, which were shown to upregulate Nav1.3. Small slow depolarizations below action potential threshold produced ramp currents, which were markedly enhanced by SCI (from 182 ± 41 to 338 ± 55 pA). The density of the noninactivating persistent sodium current was also significantly enhanced in neurons from SCI animals (from 17.4 ± 3.2 to 27.7 ± 4.4 pA/pF at 50–70 ms of depolarization). The increased persistent sodium current and ramp current, which are consistent with upregulation of Nav1.3 within dorsal horn neurons, suggest a basis for the hyperresponsiveness of these neurons following SCI.

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Abbreviations

SCI:

Spinal cord injury

DRG:

Dorsal root ganglia

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Acknowledgments

The authors thank Boris V. Safronov and Sónia F. A. Santos for their advice on surgery and slice preparation and Bart Toftness for technical assistance. This work was supported in part by grants from the Medical Research Service and Rehabilitation Research Service, Department of Veterans Affairs and the National Multiple Sclerosis Society. The Center for Neuroscience and Regeneration Research is a Collaboration of the Paralyzed Veterans of America and the United Spinal Association. AL was funded by the Epilepsy Foundation of America (Postdoctoral Research Training Fellowship). BCH was funded by The Christopher Reeve Paralysis Foundation (HB1-0304-2), the NIH/NINDS (1 F32 NS046919-01), and Pfizer (Scholar’s Grant in Pain Medicine).

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Authors and Affiliations

  1. Department of Neurology, Center for Neuroscience and Regeneration Research, Yale University School of Medicine, 333 Cedar Street, LCI-707, New Haven, CT, 06510, USA

    Angelika Lampert, Bryan C. Hains & Stephen G. Waxman

  2. Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT, 06516, USA

    Angelika Lampert, Bryan C. Hains & Stephen G. Waxman

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  1. Angelika Lampert
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  2. Bryan C. Hains
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  3. Stephen G. Waxman
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Correspondence to Stephen G. Waxman.

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Lampert, A., Hains, B.C. & Waxman, S.G. Upregulation of persistent and ramp sodium current in dorsal horn neurons after spinal cord injury. Exp Brain Res 174, 660–666 (2006). https://doi.org/10.1007/s00221-006-0511-x

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  • DOI: https://doi.org/10.1007/s00221-006-0511-x

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