Redistribution of Nav1.8 in uninjured axons enables neuropathic pain

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, Nav1.8, reverses neuropathic pain behavior after L5/L6 spinal nerve ligation (SNL), implicating a critical functional role of Nav1.8 in the neuropathic state. Here we have investigated mechanisms through which Nav1.8 contributes to the expression of experimental neuropathic pain. Nav1.8 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 Nav1.8 protein or functional channels in the cell bodies of uninjured neurons in L4 ganglia, there was a striking increase in Nav1.8 immunoreactivity along the sciatic nerve. The distribution of Nav1.8 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 μM TTX after SNL, whereas both A- and C-fiber components of sciatic nerve CAP were blocked (>90%) by 100 μM TTX in sham-operated rats or the contralateral sciatic nerve of SNL rats. Attenuating expression of Nav1.8 with antisense oligodeoxynucleotides prevented the redistribution of Nav1.8 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 Nav1.8 would be an effective treatment of neuropathic pain.