%0 Journal Article
%T Nerve growth factor, sphingomyelins, and sensitization in sensory neurons
%A Grant D. Nicol
%J ÉúÀíѧ±¨
%D 2008
%X Because nerve growth factor (NGF) is elevated duringinflammation, plays a causal role in the initiation ofhyperalgesia, and is known to activate the sphingomyelinsignalling pathway, we examined whether NGF and itsputative second messenger, ceramide, could modulate theexcitability of capsaicin-sensitive adult sensory neurons.Using the whole-cell patch-clamp recording technique,exposure of isolated sensory neurons to either 100 ng/mLNGF or 1 mmol/L N-acetyl sphingosine (C2-ceramide)produced a 3-4 fold increase in the number of action potentials(APs) evoked by a ramp of depolarizing current ina time-dependent manner. Intracellular perfusion with bacterialsphingomyelinase (SMase) also increased the numberof APs suggesting that the release of native ceramideenhanced neuronal excitability. Glutathione, an inhibitorof neutral SMase, completely blocked the NGF-inducedaugmentation of AP firing, whereas dithiothreitol, an inhibitorof acidic SMase, was without effect. In the presenceof glutathione and NGF, exogenous ceramide still enhancedthe number of evoked APs, indicating that the sensitizingaction of ceramide was downstream of NGF. Toinvestigate the mechanisms of actions for NGF andceramide, isolated membrane currents were examined.Both NGF and ceramide facilitated the peak amplitude ofthe TTX-resistant sodium current (TTX-R INa) by approximately1.5-fold and shifted the activation to morehyperpolarized voltages. In addition, NGF and ceramidesuppressed an outward potassium current (IK) by ~35%.The inflammatory prostaglandin, PGE2, produced an additionalsuppression of IK after exposure to ceramide(~35%), suggesting that these agents might act on differenttargets.Based on the existing literature, it is not clear whetherthis NGF-induced sensitization is mediated by the highaffinityTrkA receptor or the low-affinity p75 neurotrophinreceptor. Pretreatment with the p75 blocking antibodycompletely prevents the NGF-induced increase in the numberof APs evoked by the current ramp. Although thesensitization by NGF was blocked, the antibody had noeffect on the capacity of ceramide, a putative downstreamsignalling molecule, to enhance the excitability.Ceramide can be metabolized by ceramidase to sphingosine(Sph) and Sph to sphingosine 1-phosphate (S1P)by sphingosine kinase. It is well established that each ofthese products of sphingomyelin metabolism can act asintracellular signalling molecules. This raises the questionas to whether the enhanced excitability produced by NGFwas mediated directly by ceramide or required additionalmetabolism to Sph and/or S1P. Sph applied
%U http://www.actaps.com.cn/article.php?id=7185