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Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

Authors
Journal
Experimental Neurology
0014-4886
Publisher
Elsevier
Publication Date
Volume
213
Issue
2
Identifiers
DOI: 10.1016/j.expneurol.2008.06.002
Keywords
  • Nav1.8
  • Nav1.9
  • Drg
  • Sciatic Nerve
  • Cci
  • Nociceptor
  • Nerve Growth Factor
Disciplines
  • Biology
  • Chemistry

Abstract

Abstract Neuropathic pain resulting from chronic constriction injury (CCI) is critically linked to sensitization of peripheral nociceptors. Voltage gated sodium channels are major contributors to this state and their expression can be upregulated by nerve growth factor (NGF). We have previously demonstrated that neurotrophin-3 (NT-3) acts antagonistically to NGF in modulation of aspects of CCI-induced changes in trkA-associated nociceptor phenotype and thermal hyperalgesia. Thus, we hypothesized that exposure of neurons to increased levels of NT-3 would reduce expression of Na v1.8 and Na v1.9 in DRG neurons subject to CCI. In adult male rats, Na v1.8 and Na v1.9 mRNAs are expressed at high levels in predominantly small to medium size neurons. One week following CCI, there is reduced incidence of neurons expressing detectable Na v1.8 and Na v1.9 mRNA, but without a significant decline in mean level of neuronal expression, and similar findings observed immunohistochemically. There is also increased accumulation/redistribution of channel protein in the nerve most apparent proximal to the first constriction site. Intrathecal infusion of NT-3 significantly attenuates neuronal expression of Na v1.8 and Na v1.9 mRNA contralateral and most notably, ipsilateral to CCI, with a similar impact on relative protein expression at the level of the neuron and constricted nerve. We also observe reduced expression of the common neurotrophin receptor p75 in response to CCI that is not reversed by NT-3 in small to medium sized neurons and may confer an enhanced ability of NT-3 to signal via trkA, as has been previously shown in other cell types. These findings are consistent with an analgesic role for NT-3.

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