Brain-derived neurotrophic factor enhances the excitability of rat sensory neurons through activation of the p75 neurotrophin receptor and the sphingomyelin pathway

Y. H. Zhang, Xian Xuan Chi, G. D. Nicol

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Neurotrophin-mediated signalling cascades can be initiated by activation of either the p75 neurotrophin receptor (p75NTR) or the more selective tyrosine kinase receptors. Previously, we demonstrated that nerve growth factor (NGF) increased the excitability of sensory neurons through activation of p75NTR to liberate sphingosine 1-phosphate. If neurotrophins can modulate the excitability of small diameter sensory neurons through activation of p75NTR, then brain-derived neurotrophic factor (BDNF) should produce the same sensitizing action as did NGF. In this report, we show that focally applied BDNF increases the number of action potentials (APs) evoked by a ramp of depolarizing current by reducing the rheobase without altering the firing threshold. This increased excitability results, in part, from the capacity of BDNF to enhance a tetrodotoxin-resistant sodium current (TTX-R INa) and to suppress a delayed rectifier-like potassium current (IK). The idea that BDNF acts via p75NTR is supported by the following observations. The sensitizing action of BDNF is prevented by pretreatment with a blocking antibody to p75NTR or an inhibitor of sphingosine kinase (dimethylsphingosine), but not by inhibitors of tyrosine kinase receptors (K252a or AG879). Furthermore, using single-cell RT-PCR, neurons that were sensitized by BDNF expressed the mRNA for p75NTR but not TrkB. These results demonstrate that neurotrophins can modulate the excitability of small diameter capsaicin-sensitive sensory neurons through the activation of p75NTR and its downstream sphingomyelin signalling cascade. Neurotrophins released upon activation of a variety of immuno-competent cells may be important mediators that give rise to the enhanced neuronal sensitivity associated with the inflammatory response.

Original languageEnglish (US)
Pages (from-to)3113-3127
Number of pages15
JournalJournal of Physiology
Volume586
Issue number13
DOIs
StatePublished - Jul 1 2008

ASJC Scopus subject areas

  • Physiology

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