New NT3 neuropathic pain research

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Exp Neurol. 2008 Oct;213(2):303-14.

Neurotrophin-3 significantly reduces sodium channel expression linked

to neuropathic pain states.

-Gerwing TD, Stucky CL, McComb GW, Verge VM.

Department of Anatomy and Cell Biology, Cameco MS Neuroscience

Research Center University of Saskatchewan, Saskatoon, Saskatchewan,

Canada.

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(v)1.8 and Na(v)

1.9 in DRG neurons subject to CCI.

In adult male rats, Na(v)1.8 and Na(v)1.9 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(v)1.8 and Na(v)1.9 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(v)1.8 and Na(v)1.9 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.