Altered expression of sodium channel distribution in the dorsal root ganglion after gradual elongation of rat sciatic nerves

Abstract

To elucidate the pathophysiological mechanisms underlying chronic nerve-stretch injury, we gradually lengthened rat femurs by 15 mm at the rate of 0.5 mm/day (group L, n ¼ 13). The control groups comprised sham-operated (group S, n ¼ 10) and naive (group N, n ¼ 8) rats. Immediately after the lengthening, we performed a conduction study on their sciatic nerves and harvested samples. Electrophysiological and histological analyses showed mild conduction slowing and axonal degeneration of unmyelinated fibers in group L rats. Altered mRNA expression of the voltage-gated sodium channels in the dorsal root ganglion was also observed. Tetrodotoxin-resistant (TTX-R) sodium-channel Nav1.8 mRNA expression was significantly decreased and TTX-R sodium-channel Nav1.9 mRNA expression showed a tendency to decrease when compared with the mRNA expressions in the control groups. However, tetrodotoxin-sensitive (TTX-S) sodiumchannel Nav1.3 mRNA expression remained unaltered. The immunohistochemical alteration of Nav1.8 protein expression was parallel to the results of the mRNA expression. Previous studies involving neuropathic states have suggested that pain/paresthesia is modulated by a subset of sodium channels, including downregulation and/or upregulation of TTX-R and TTX-S sodium channels, respectively. Our findings indicate that Nav1.8 downregulation may be one of the pathophysiological mechanisms involved in limb lengthening-induced neuropathy. Keywords: sodium channel; limb lengthening; peripheral nerve; nerve elongation; dorsal root ganglion Limb lengthening is a popular method of treating leg length discrepancies or congenital anomalies, but the technique could cause peripheral nerve injury. Gradual nerve elongation is believed to be the primary cause of this form of injury because studies have demonstrated a clear correlation between the extent of lengthening and the degree of conduction slowing.1,2 However, most of these basic studies have considered only the morphological and electrophysiological alterations in the elongated nerve; 3,4 therefore, the pathophysiological mechanisms underlying chronic nerve-stretch injury are not fully understood.Clinically, the earliest symptom of neuropathy induced by limb lengthening is pain and/or paresthesia along the leg's sensory nerve distribution, 5 similar to neuropathy induced by other types of injuries. Several experimental models have been proposed for various types of nerve injuries, such as the axotomy model 6 and the sciatic nerve or spinal nerve ligation model. 7-9 These studies have identified that the underlying pathophysiology after nerve injury is closely associated with altered expression of the voltage-gated sodium channels (VGSCs) in the dorsal root ganglion (DRG). 10-12VGSCs consist of alpha and beta subunits. The mature channels in the plasma membrane are mainly composed of alpha subunits, 13 which have been further classified into two types on the basis of the differences in their physiological and pharmacological properties: tetrodotoxin-resistant (TTX...

Tetrodotoxin (TTX) as a Therapeutic Agent for Pain

“…In support of this finding, the injured DRG and sciatic nerve in this pain model showed reduced Na v 1.7 protein and/or mRNA expression in rodents [45,73,82,83,84]. Na v 1.7 protein expression was also downregulated in trigeminal ganglion of ferrets after trigeminal nerve injury [74]. However, two groups reported a significant increase in Na v 1.7 protein expression in the DRG neurons of rats with painful diabetic neuropathy [56,97], although another study found no change in Na v 1.7 mRNA expression [54].…”

“…For example, although the immunoreactive expression of Na v 1.3 was found to be upregulated in neuromas from humans [42] and rats [35], little change was observed in neuromas from mice [72]. Moreover, rat studies found no significant change in Na v 1.3 mRNA levels after unilateral sciatic nerve entrapment injury [73] or gradual elongation of sciatic nerve [74]. Downregulation of Na v 1.3 was even reported in the trigeminal ganglia in a ferret model of trigeminal neuropathic pain [75].…”

Regulation of voltage-gated ion channels in excitable cells by the ubiquitin ligases Nedd4 and Nedd4-2

“…For example, conditions such as epilepsy and pain are due to abnormal regulation of sodium channels by the ubiquitin proteasome system (UPS). [44][45][46][47] A deeper understanding of the molecular mechanisms involved in the UPS mediated degradation of proteins and ion channels may provide novel insights into mechanisms that may alleviate these debilitating diseases. It is important to note, that although there is ample evidence implicating the UPS in neurological diseases, the molecular identity of the ligases and associated proteins remains largely unknown.…”

Whatʼs New in Pediatric Orthopaedics

“…Kitoh et al, in a study investigating the clinical efficacy of culture-expanded bone marrow cell and platelet-rich plasma injected into patients undergoing tibial and femoral lengthening, demonstrated a decreased healing index, dependent on osteoblastic differentiation of bone marrow cells39 . Ohno et al, in an investigation of the effect of distraction on the rat sciatic nerve, showed slower conduction and axonal degeneration of unmyelinated fibers as well as downregulation of mRNA expression of tetrodotoxin-resistanttype sodium-channel Nav1.8 mRNA in dorsal root ganglion, a finding associated with pain and paresthesia in other studies of neuropathy40 .…”