Na+ channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation.
Nerve injury frequently triggers hyperexcitability and the ectopic initiation of impulses in primary afferent axons. An important consequence is neuropathic paresthesias and pain. Electrogenesis in normal afferents depends on appropriate Na+ channel concentrations. Therefore, we have asked whether injury might trigger changes in axolemmal Na+ channel distribution that could account for neuropathic hyperexcitability. We used an Na+ channel-specific antibody, 7493, to immunolocalize Na+ channels ultrastructurally in membranes of normal rat axons, and to assess remodeling following nerve section and neuroma formation. Selective labeling of nodal axolemma and, more weakly, of Schwann cell membrane, confirmed the efficacy of our immunolabeling protocol. In neuromas at postoperative times associated with peak ectopic activity, we found clear evidence of Na+ channel accumulation. Specifically, soon after myelin was stripped from large-diameter axons, the exposed, formerly internodal axolemma became immunopositive. Small-diameter unmyelinated axons and axon sprouts in the neuroma were also marked with 7493 IgG. Activated phagocytic macrophages and endothelial cells were 7493 negative. Both large- and small-diameter axons in neuromas end in swollen, organelle-packed "end bulbs." Most, but not all, of these acquired Na+ channel immunolabeling. We propose that remodeling results from a modification of the normal process of Na+ channel turnover in neural membranes. Na+ channel protein accumulates in preterminal axolemma and neuroma end bulbs due to a combination of permissive factors (especially myelin removal) and promotional factors (removal of normal downstream targets). This accumulation is a likely precursor of afferent hyperexcitability in injured nerve.
Devor
M
M
Department of Cell and Animal Biology, Life Sciences Institute, Hebrew University of Jerusalem, Israel.
Govrin-Lippmann
R
R
Angelides
K
K
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology; D000939:Epitopes; D007158:Immunologic Techniques; D008297:Male; D009186:Myelin Sheath / Q000502:physiology; D009463:Neuroma / Q000378:metabolism*; D009473:Neuronal Plasticity; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000378:metabolism*; D010524:Peripheral Nervous System Neoplasms / Q000378:metabolism*; D011901:Ranvier's Nodes / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000276:immunology / Q000378:metabolism*; D014950:Wounds, Penetrating / Q000378:metabolism
D000939:Epitopes; D015222:Sodium Channels