The pattern of expression of the voltage-gated sodium channels Nav1.8 and Nav1.9 does not change in uninjured primary sensory neurons in experimental neuropathic pain models

Abstract

A spared nerve injury of the sciatic nerve (SNI) or a segmental lesion of the L5 and L6 spinal nerves (SNL) lead to behavioral signs of neuropathic pain in the territory innervated by adjacent uninjured nerve fibers, while a chronic constriction injury (CCI) results in pain sensitivity in the affected area. While alterations in voltage-gated sodium channels (VGSCs) have been shown to contribute to the generation of ectopic activity in the injured neurons, little is known about changes in VGSCs in the neighboring intact dorsal root ganglion (DRG) neurons, even though these cells begin to fire spontaneously. We have now investigated changes in the expression of the TTX-resistant VGSCs, Nav1.8 (SNS/PN3) and Nav1.9 (SNS2/NaN) by immunohistochemistry in rat models of neuropathic pain both with an intermingling of intact and degenerated axons in the nerve stump (SNL and CCI) and with a co-mingling in the same DRG of neurons with injured and uninjured axons (sciatic axotomy and SNI). The expression of Nav1.8 and Nav1.9 protein was abolished in all injured DRG neurons, in all models. In intact DRGs and in neighboring non-injured neurons, the expression and the distribution among the A- and C-fiber neuronal populations of Nav1.8 and Nav1.9 was, however, unchanged. While it is unlikely, therefore, that a change in the expression of TTX-resistant VGSCs in non-injured neurons contributes to neuropathic pain, it is essential that molecular alterations in both injured and non-injured neurons in neuropathic pain models are investigated.

Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

“…These findings are consistent with the decreased incidence of expression observed in the small sized DRG neurons observed by Dib-Hajj et al (1999), and the decrease in the large sized neurons (presumably those axotomized by CCI) reported by Decosterd et al (2002). The mean labeling index for these neurons, however, was not significantly decreased following CCI (33.29 +/− 7.145 in the intact to 27.23 +/− 6.756 following CCI; p<0.001; Figure 4) and is probably reflective of the increased expression observed in a subpopulation of small to medium size neurons.…”

“…The decreased incidence of expression, consistent with the findings of Dib-Hajj et al(1999), occurs primarily in the small to medium diameter neurons (Table 1). The smaller decrease in incidence of expression in the larger cells (presumably those axotomized by CCI) is in agreement with that observed by Decosterd et al (2002).…”

“…Reported alterations in the expression of both Na v 1.8 and Na v 1.9 in response to chronic constriction injury (CCI) are conflicting (Novakovic et al, 1998;Dib-Hajj et al, 1999;Decosterd et al, 2002), and the channels respond differently to inflammation (Tanaka et al, 1998;Black et al, 2004;Gould et al, 2004). This may be due to the complexity of the CCI model which produces preferential axotomy of large sized DRG neurons and exposure of the remaining intact axons to an inflammatory environment (Bennett and Xie, 1988;Kajander and Bennett, 1992) with increased levels of nerve growth factor (NGF) that increase injury-induced expression of these channels Fjell et al, 1999).…”

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

“…To discriminate injured and non-injured neurons in the same DRGs, we used a strategy combining retrograde tracing of the intact sural nerve and immunohistochemical detection of injured neurons with antibody to ATF3 (a marker of axonal injury) (Benn et al, 2002;Decosterd et al, 2002;Obata et al, 2004). As expected, 1 week after SNI, significant ATF3 immunoreactivity was present but did not overlap with Fluorogold (Fig.…”

The Voltage-Gated Sodium Channel Nav1.9 Is an Effector of Peripheral Inflammatory Pain Hypersensitivity

“…Na v 1.9 expression is downregulated in injured neurons (Tate et al, 1998;Dib-Hajj et al, 1999) without a significant change in neighboring uninjured neurons (Decosterd et al, 2002). A Na v 1.8 and Na v 1.7 double knock-out mouse continues to show substantial hyperalgesia after nerve injury (Nassar et al, 2005).…”