Changes in Expression of Two Tetrodotoxin-Resistant Sodium Channels and Their Currents in Dorsal Root Ganglion Neurons after Sciatic Nerve Injury But Not Rhizotomy

Abstract

Two TTX-resistant sodium channels, SNS and NaN, are preferentially expressed in c-type dorsal root ganglion (DRG) neurons and have been shown recently to have distinct electrophysiological signatures, SNS producing a slowly inactivating and NaN producing a persistent sodium current with a relatively hyperpolarized voltage-dependence. An attenuation of SNS and NaN transcripts has been demonstrated in small DRG neurons after transection of the sciatic nerve. However, it is not known whether changes in the currents associated with SNS and NaN or in the expression of SNS and NaN channel protein occur after axotomy of the peripheral projections of DRG neurons or whether similar changes occur after transection of the central (dorsal root) projections of DRG neurons. Peripheral and central projections of L4/5 DRG neurons in adult rats were axotomized by transection of the sciatic nerve and the L4 and L5 dorsal roots, respectively. DRG neurons were examined using immunocytochemical and patch-clamp methods 9-12 d after sciatic nerve or dorsal root lesion. Levels of SNS and NaN protein in the two types of injuries were paralleled by their respective TTX-resistant currents. There was a significant decrease in SNS and NaN signal intensity in small DRG neurons after peripheral, but not central, axotomy compared with control neurons. Likewise, there was a significant reduction in slowly inactivating and persistent TTX-resistant currents in these neurons after peripheral, but not central, axotomy compared with control neurons. These results indicate that peripheral, but not central, axotomy results in a reduction in expression of functional SNS and NaN channels in c-type DRG neurons and suggest a basis for the altered electrical properties that are observed after peripheral nerve injury.

Upregulation of the Voltage-Gated Sodium Channel β2 Subunit in Neuropathic Pain Models: Characterization of Expression in Injured and Non-Injured Primary Sensory Neurons

“…␤2 subunit mRNA levels in L4/L5 DRGs did not change over the 7 d after SNI ( p Ͼ 0.05; n ϭ 4 -6 in each group). As expected from other studies (Black et al, 1999;Sleeper et al, 2000), Na v 1.8 mRNA significantly decreased 7 d after SNI compared with control ( p Ͻ 0.05), and the level of Na v 1.3 mRNA significantly increased at 7 d after SNI ( p Ͻ 0.05). The unchanged level of ␤2 subunit mRNA after SNI was confirmed by isotopic in situ hybridization studies using two separate sets of radiolabeled probes and performed 1 week after SNI or 2 weeks after SNL (Fig.…”

“…This parallels the emergence of a rapidly repriming TTX-sensitive sodium current in injured neurons that may contribute to a spontaneous firing of DRG neurons or firing at unusually higher frequencies (Black et al, 1999;Cummins et al, 2001;Takahashi et al, 2003). In contrast, TTX-resistant sodium currents and Na v 1.8 and Na v 1.9 channel expression decrease in injured neurons (Sleeper et al, 2000;Decosterd et al, 2002). TTX-resistant channels persist in intact adjacent neurons , and Na v 1.8 is redistributed in the spared nerve so that this channel may contribute to pain hypersensitivity (Gold et al, 2003).…”

Contactin Associates with Sodium Channel Nav1.3 in Native Tissues and Increases Channel Density at the Cell Surface

“…To ensure that the elevated contactin signal in the ipsilateral sample is not an artifact of sample preparation or gel loading, the blot was stripped and reprobed with anti-Na v 1.9 antibody. We have shown previously that Na v 1.9 expression at the levels of RNA and protein are significantly downregulated after transection of the sciatic nerve (Dib-Hajj et al, 1998;Sleeper et al, 2000;Tyrrell et al, 2001). As expected, Na v 1.9 protein level in the ipsilateral DRG sample (Fig.…”

Phosphorylation of Sodium Channel Nav1.8 by p38 Mitogen-Activated Protein Kinase Increases Current Density in Dorsal Root Ganglion Neurons

“…We have shown in this study that a subset of small diameter DRG neurons, which are known to produce Na v 1.8 (Fjell et al, 1999;Amaya et al, 2000;Sleeper et al, 2000;Rush et al, 2005b), also produce activated p38 MAPK. Given the central role of Na v 1.8 in action potential firing Blair and Bean, 2002), the increase in the slowly inactivating TTX-R current density, which is mediated by direct phosphorylation of Na v 1.8 channels by p38 MAPK, can increase DRG neuron excitability under pathological conditions.…”