PMID- 18450779 OWN - NLM STAT- MEDLINE DCOM- 20081113 LR - 20211020 IS - 1469-7793 (Electronic) IS - 0022-3751 (Print) IS - 0022-3751 (Linking) VI - 586 IP - 13 DP - 2008 Jul 1 TI - Brain-derived neurotrophic factor enhances the excitability of rat sensory neurons through activation of the p75 neurotrophin receptor and the sphingomyelin pathway. PG - 3113-27 LID - 10.1113/jphysiol.2008.152439 [doi] AB - Neurotrophin-mediated signalling cascades can be initiated by activation of either the p75 neurotrophin receptor (p75(NTR)) or the more selective tyrosine kinase receptors. Previously, we demonstrated that nerve growth factor (NGF) increased the excitability of sensory neurons through activation of p75(NTR) to liberate sphingosine 1-phosphate. If neurotrophins can modulate the excitability of small diameter sensory neurons through activation of p75(NTR), 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 I(Na)) and to suppress a delayed rectifier-like potassium current (I(K)). The idea that BDNF acts via p75(NTR) is supported by the following observations. The sensitizing action of BDNF is prevented by pretreatment with a blocking antibody to p75(NTR) 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 p75(NTR) but not TrkB. These results demonstrate that neurotrophins can modulate the excitability of small diameter capsaicin-sensitive sensory neurons through the activation of p75(NTR) 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. FAU - Zhang, Y H AU - Zhang YH AD - Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. FAU - Chi, Xian Xuan AU - Chi XX FAU - Nicol, G D AU - Nicol GD LA - eng GR - C06 RR015481/RR/NCRR NIH HHS/United States GR - R01 NS046084/NS/NINDS NIH HHS/United States GR - NS46084/NS/NINDS NIH HHS/United States GR - C06 RR015481-01/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20080501 PL - England TA - J Physiol JT - The Journal of physiology JID - 0266262 RN - 0 (AG-879) RN - 0 (Antibodies) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Carbazoles) RN - 0 (Enzyme Inhibitors) RN - 0 (Indole Alkaloids) RN - 0 (RNA, Messenger) RN - 0 (Receptor, Nerve Growth Factor) RN - 0 (Sodium Channels) RN - 0 (Sphingomyelins) RN - 0 (Tyrphostins) RN - 4368-28-9 (Tetrodotoxin) RN - 97161-97-2 (staurosporine aglycone) RN - EC 2.7.10.1 (Receptor, trkB) RN - L9QRA71834 (N,N-dimethylsphingosine) RN - NGZ37HRE42 (Sphingosine) SB - IM MH - Action Potentials MH - Animals MH - Antibodies MH - Brain-Derived Neurotrophic Factor/*pharmacology MH - Carbazoles/pharmacology MH - Enzyme Inhibitors/pharmacology MH - Gene Expression Regulation/physiology MH - Indole Alkaloids/pharmacology MH - Male MH - Neurons, Afferent/*physiology MH - RNA, Messenger/genetics/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Receptor, Nerve Growth Factor/*physiology MH - Receptor, trkB/genetics/metabolism MH - Signal Transduction/*physiology MH - Sodium Channels/metabolism MH - Sphingomyelins/*metabolism MH - Sphingosine/analogs & derivatives/pharmacology MH - Tetrodotoxin MH - Tyrphostins/pharmacology PMC - PMC2538774 EDAT- 2008/05/03 09:00 MHDA- 2008/11/14 09:00 PMCR- 2009/07/01 CRDT- 2008/05/03 09:00 PHST- 2008/05/03 09:00 [pubmed] PHST- 2008/11/14 09:00 [medline] PHST- 2008/05/03 09:00 [entrez] PHST- 2009/07/01 00:00 [pmc-release] AID - jphysiol.2008.152439 [pii] AID - 10.1113/jphysiol.2008.152439 [doi] PST - ppublish SO - J Physiol. 2008 Jul 1;586(13):3113-27. doi: 10.1113/jphysiol.2008.152439. Epub 2008 May 1.