Abstract
BackgroundNeuropathic pain caused by peripheral nerve injury is a chronic disorder that represents a significant clinical challenge because the pathological mechanisms have not been fully elucidated. Several studies have suggested the involvement of various sodium channels, including tetrodotoxin-resistant NaV1.8, in affected dorsal root ganglion (DRG) neurons. We have hypothesized that altered local expression of NaV1.8 in the peripheral axons of DRG neurons could facilitate nociceptive signal generation and propagation after neuropathic injury.ResultsAfter unilateral sciatic nerve entrapment injury in rats, compound action potential amplitudes were increased in both myelinated and unmyelinated fibers of the ipsilateral sciatic nerve. Tetrodotoxin resistance of both fiber populations and sciatic nerve NaV1.8 immunoreactivity were also increased. Further analysis of NaV1.8 distribution revealed that immunoreactivity and mRNA levels were decreased and unaffected, respectively, in the ipsilateral L4 and L5 DRG; however sciatic nerve NaV1.8 mRNA showed nearly an 11-fold ipsilateral increase. Nav1.8 mRNA observed in the sciatic nerve was likely of axonal origin since it was not detected in non-neuronal cells cultured from nerve tissue. Absence of changes in NaV1.8 mRNA polyadenylation suggests that increased mRNA stability was not responsible for the selective peripheral mRNA increase. Furthermore, mRNA levels of NaV1.3, NaV1.5, NaV1.6, NaV1.7, and NaV1.9 were not significantly different between ipsilateral and contralateral nerves. We therefore propose that selective NaV1.8 mRNA axonal transport and local up-regulation could contribute to the hyperexcitability of peripheral nerves in some neuropathic pain states.ConclusionCuff entrapment injury resulted in significantly elevated axonal excitability and increased NaV1.8 immunoreactivity in rat sciatic nerves. The concomitant axonal accumulation of NaV1.8 mRNA may play a role in the pathogenesis of this model of neuropathic pain.
Highlights
Neuropathic pain caused by peripheral nerve injury is a chronic disorder that represents a significant clinical challenge because the pathological mechanisms have not been fully elucidated
Loss-of-function studies using antisense oligodeoxynucleotides and siRNA have highlighted the importance of the NaV1.8 tetrodotoxin resistant (TTX-r) sodium channel in the neurophysiological and behavioral effects observed in spinal nerve ligation (SNL) and chronic constriction injury (CCI) models of peripheral neuropathy [4,5,6,7]
Sciatic nerve excitability and TTX-resistance after sciatic nerve entrapment (SNE) The compound action potential (CAP) response amplitudes from contralateral, naïve control nerves, and ipsilateral sham nerves were similar and grouped together. 2 weeks after SNE, the amplitudes of both A- and C-fiber CAPs were significantly increased in ipsilateral sciatic nerves when compared to control, sham or contralateral nerves (Fig. 1)
Summary
Neuropathic pain caused by peripheral nerve injury is a chronic disorder that represents a significant clinical challenge because the pathological mechanisms have not been fully elucidated. Several studies have suggested the involvement of various sodium channels, including tetrodotoxin-resistant NaV1.8, in affected dorsal root ganglion (DRG) neurons. Several peripheral nerve injury-based rat models have been developed that exhibit various behavioral characteristics representative of neuropathic symptomatology, including hindpaw hypersensitivity to mechanical and thermal stimuli [3]. Loss-of-function studies using antisense oligodeoxynucleotides and siRNA have highlighted the importance of the NaV1.8 tetrodotoxin resistant (TTX-r) sodium channel in the neurophysiological and behavioral effects observed in spinal nerve ligation (SNL) and chronic constriction injury (CCI) models of peripheral neuropathy [4,5,6,7]. It has been found that NaV1.8-null transgenic mice do not exhibit abnormal neurophysiology in injured neuroma tissue [14]
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