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J Neurosci. 2003 Jan 1;23(1):158-66.

Redistribution of Na(V)1.8 in uninjured axons enables neuropathic pain.

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  • 1Department of Oral and Craniofacial Biological Sciences, University of Maryland, Baltimore, Maryland 21201, USA. msg001@dental.umaryland.edu

Abstract

The underlying mechanisms of neuropathic pain are poorly understood, and existing treatments are mostly ineffective. We recently demonstrated that antisense mediated "knock-down" of the sodium channel isoform, Na(V)1.8, reverses neuropathic pain behavior after L5/L6 spinal nerve ligation (SNL), implicating a critical functional role of Na(V)1.8 in the neuropathic state. Here we have investigated mechanisms through which Na(V)1.8 contributes to the expression of experimental neuropathic pain. Na(V)1.8 does not appear to contribute to neuropathic pain through an action in injured afferents because the channel is functionally downregulated in the cell bodies of injured neurons and does not redistribute to injured terminals. Although there was little change in Na(V)1.8 protein or functional channels in the cell bodies of uninjured neurons in L4 ganglia, there was a striking increase in Na(V)1.8 immunoreactivity along the sciatic nerve. The distribution of Na(V)1.8 reflected predominantly the presence of functional channels in unmyelinated axons. The C-fiber component of the sciatic nerve compound action potential (CAP) was resistant (>40%) to 100 microm TTX after SNL, whereas both A- and C-fiber components of sciatic nerve CAP were blocked (>90%) by 100 microm TTX in sham-operated rats or the contralateral sciatic nerve of SNL rats. Attenuating expression of Na(V)1.8 with antisense oligodeoxynucleotides prevented the redistribution of Na(V)1.8 in the sciatic nerve and reversed neuropathic pain. These observations suggest that aberrant activity in uninjured C-fibers is a necessary component of pain associated with partial nerve injury. They also suggest that blocking Na(V)1.8 would be an effective treatment of neuropathic pain.

PMID:
12514212
[PubMed - indexed for MEDLINE]
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