Glial-derived neurotrophic factor upregulates expression of functional SNSand NaN sodium channels and their currents in axotomized dorsal root ganglion neurons

Dorsal root ganglion (DRG) neurons produce multiple sodium currents, includ ing several different TTX-sensitive (TTX-S) currents and TTX-resistant (TTX -R) currents, which are produced by distinct sodium channels. We previously demonstrated that, after sciatic nerve transection, the levels of SNS and NaN sodium channel alpha -subunit transcripts and protein in small (18-30 m um diameter) DRG neurons are reduced, as are the amplitudes and densities o f the slowly inactivating and persistent TTX-R currents produced by these t wo channels. In this study, we asked whether glial-derived neurotrophic fac tor (GDNF), which has been shown to prevent some axotomy-induced changes su ch as the loss of somatostatin expression in DRG neurons, can ameliorate th e axotomy-induced downregulation of SNS and NaN TTX-R sodium channels. We s how here that exposure to GDNF can significantly increase both slowly inact ivating and persistent TTX-R sodium currents, which are paralleled by incre ases in SNS and NaN mRNA and protein levels, in axotomized DRG neurons in v itro. We also show that intrathecally administered GDNF increases the ampli tudes of the slowly inactivating and persistent TTX-R currents, and SNS and NaN protein levels, in peripherally axotomized DRG neurons in vivo. Finall y, we demonstrate that GDNF upregulates the persistent TTX-R current in SNS -null mice, thus demonstrating that the upregulated persistent sodium curre nt is not produced by SNS. Because TTX-R sodium channels have been shown to be important in nociception, the effects of GDNF on axotomized DRG neurons may have important implications for the regulation of nociceptive signalin g by these cells.