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J Neurophysiol 88: 650-658, 2002;
0022-3077/02 $5.00
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The Journal of Neurophysiology Vol. 88 No. 2 August 2002, pp. 650-658
Copyright ©2002 by the American Physiological Society

GDNF and NGF Reverse Changes in Repriming of TTX-Sensitive Na+ Currents Following Axotomy of Dorsal Root Ganglion Neurons

Andreas Leffler, Theodore R. Cummins, Sulayman D. Dib-Hajj, William N. Hormuzdiar, Joel A. Black, and Stephen G. Waxman

Department of Neurology and Paralyzed Veterans of America/Eastern Paralyzed Veterans Association Neuroscience Research Center, Yale Medical School, New Haven 06510; and Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut 06516

Leffler, Andreas, Theodore R. Cummins, Sulayman D. Dib-Hajj, William N. Hormuzdiar, Joel A. Black, and Stephen G. Waxman. GDNF and NGF Reverse Changes in Repriming of TTX-Sensitive Na+ Currents Following Axotomy of Dorsal Root Ganglion Neurons. J. Neurophysiol. 88: 650-658, 2002. Uninjured C-type rat dorsal root ganglion (DRG) neurons predominantly express slowly inactivating TTX-resistant (TTX-R) and slowly repriming TTX-sensitive (TTX-S) Na+ currents. After peripheral axotomy, TTX-R current density is reduced and rapidly repriming TTX-S currents emerge and predominate. The change in TTX-S repriming kinetics is paralleled by an increase in the level of transcripts and protein for the Nav1.3 sodium channel alpha -subunit, which is known to exhibit rapid repriming. Changes in Na+ current profile and kinetics in DRG neurons may substantially alter neuronal excitability and could contribute to some states of chronic pain associated with injury of sensory neurons. In the present study, we asked whether glial-derived neurotrophic factor (GDNF) and nerve growth factor (NGF), which have been shown to prevent some axotomy-induced changes such as the loss of TTX-R Na+ current expression in DRG neurons, can ameliorate the axotomy-induced change in TTX-S Na+ current repriming kinetics. We show that intrathecally administered GDNF and NGF, delivered individually, can partially reverse the effect of axotomy on the repriming kinetics of TTX-S Na+ currents. When GDNF and NGF were co-administered, the repriming kinetics were fully rescued. We observed parallel effects of GDNF and NGF on the Nav1.3 sodium channel transcript levels in axotomized DRG. Both GDNF and NGF were able to partially reverse the axotomy-induced increase in Nav1.3 mRNA, with GDNF plus NGF producing the largest effect. Our data indicate that both GDNF and NGF can partially reverse an important effect of axotomy on the electrogenic properties of sensory neurons and that their effect is additive.




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