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...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.