Sodium channel accumulation in humans with painful neuromas

England, John D.; Happel, Leo T.; Kline, David G.; Gamboni, Fabia; Thouron, Carol L.; Liu, Z. P.; Levinson, S. R.

doi:10.1212/wnl.47.1.272

Cited by 175 publications

(84 citation statements)

References 5 publications

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“…The common sciatic nerves at the level of the CCI with or without NT-3 infusion were processed to detect either Na v 1.8 or Na v 1.9 protein. Consistent with previous reports (Devor et al, 1989;England et al, 1994England et al, , 1996Amir et al, 1999), both Na v 1.8 and Na v 1.9 protein levels were more highly localized to the constriction sites 7 days following CCI (CCI; Figure 7 bottom). Infusion of NT-3 attenuated this redistribution as evidenced by a reduction in relative levels of Na v 1.8 and Na v 1.9 protein at the constriction sites of the CCI + NT-3 treated nerves (Figure 7 bottom).…”

Section: Nt-3 Significantly Attenuates Neuronal Na V 18 Mrna Expressionsupporting

confidence: 91%

“…Interestingly, it appears that Na v 1.9 does play a role in hypersensitivity produced by the application of inflammatory mediators to the peripheral terminals of the nociceptors (Amaya et al, 2006). It has been proposed that Na v 1.9 plays a crucial role in setting the resting membrane potential of a neuron and that an increased density of this channel, such as is seen with the accumulation of voltage gated sodium channels at the tips of the injured neurons (Devor et al, 1989;England et al, 1994England et al, , 1996, may hyperpolarize the neuron (Herzog et al, 2001). It thus appears that the decreased expression of Na v 1.8 by exogenous NT-3 likely plays an important role in preventing the development of thermal hyperalgesia, while the decreased expression of Na v 1.9 may prevent hyperexcitablity and/or repetitive firing of the neuron by increasing the resting membrane potential of these neurons.…”

Section: Discussionmentioning

confidence: 99%

“…NT-3 effects a decrease in Na v 1.8 and Na v 1.9 protein in the nerve and neuroma Following nerve injury, voltage gated sodium channels are highly localized/redistributed to the tips of the injured axons and/or neuromas despite a lower level of expression in the cell body of these neurons (Devor et al, 1989;England et al, 1994England et al, , 1996Amir et al, 1999). Thus, we asked whether the dramatic reduction in sodium channel expression effected by NT-3 in neurons ipsilateral to CCI is also reflected in a reduced localization of these channels to the neuroma at the constriction sites formed by the ligatures, unlike that observed for CCI alone.…”

Section: Nt-3 Significantly Attenuates Neuronal Na V 18 Mrna Expressionmentioning

confidence: 99%

“…It is well established that both the activation threshold of a neuron and the potential for spontaneous firing is regulated by sodium channels (Hodgkin and Huxley, 1952;Catterall, 1995). This hyperexcitability of sensory neurons following nerve injury has been associated with altered expression and the redistribution of voltage gated sodium channels to the tips of the injured axons and/or the neuromas (Devor et al, 1989;England et al, 1994England et al, , 1996Amir et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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

Wilson-Gerwing

Stucky

McComb

et al. 2008

Experimental Neurology

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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.

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Section: Nt-3 Significantly Attenuates Neuronal Na V 18 Mrna Expressionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Nt-3 Significantly Attenuates Neuronal Na V 18 Mrna Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Wilson-Gerwing

Stucky

McComb

et al. 2008

Experimental Neurology

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“…Other studies using immunocytochemical methods have demonstrated increased numbers of sodium channels within the distal parts of injured axons. [12][13][14] Contemporary molecular techniques have recently allowed us to examine the molecular basis for these changes and to ask whether different types of sodium channels are deployed within neurons following injury ( Figure 2). We have thus learned that there is an upregulation of several sodium channel genes, including the previously silent ␣-III sodium channel gene 15 and a down-regulation of other sodium channel genes, including ␣-SNS and NaN in DRG neurons following axonal transection (Figure 2).…”

Section: Sodium Channel Expression Is Dynamic: I Developing and Injumentioning

confidence: 99%

The molecular basis for electrogenic computation in the brain: you can't step in the same river twice

Waxman

1999

Mol Psychiatry

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Neural computation has classically been considered to be a process that depends, in large part, on the integration of excitatory and inhibitory synaptic signals by postsynaptic neurons; these cells generate sequences of action potentials that convey their messages, in turn, to still other neurons. We now appreciate that synaptic activity is a dynamic process that can be altered by mechanisms that include sprouting, pruning, facilitation, potentiation, and depression. But what about the electrogenic properties of neurons, ie the capability of these cells to generate all-or-non action potentials? Recent work indicates that the electrogenic machinery within neurons is also dynamic as a result of plasticity in the expression of sodium channels within the neuronal membrane. Molecular and functional remodeling of electrogenic membrane has been most extensively studied in developing and diseased neurons, but also occurs in the normal brain. The molecular plasticity of electrogenic membrane has important functional implications, since it can retune the neuron, changing its input-output relations.Keywords: sodium channels; action potential electrogenesis; neural coding; information processing; CNS plasticityThe ten billion neurons within the brain and spinal cord form a computer that is more complex and flexible than any device produced thus far by man. According to the classical Sherringtonian model, each neuron integrates incoming information so as to generate a sequence of regenerative action potentials that conveys its message to other neurons. Information processing in the central nervous system, according to this model, involves the generation of complex patterns of action potentials by neurons which integrate the activity at excitatory and inhibitory synapses which impinge upon them. Synaptic mechanisms underlying these excitatory and inhibitory effects have been studied in detail-indeed, we now understand not only the steady-state behavior of synapses, but also appreciate that synaptic activity is a dynamic process that can be altered by mechanisms that include sprouting, pruning, facilitation, potentiation and depression.Since electrogenicity, ie, the capability of neurons to generate action potentials, contributes substantially to their integrative function, an understanding of its molecular basis may provide insights into the molecular underpinnings of higher function. The seminal work of Hodgkin and Huxley demonstrated that, in most neurons, voltage-gated sodium channels are responsible for the regenerative depolarization that underlies the Correspondence: SG Waxman, MD, PhD, Department of Neurology, LCI 707,

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Sodium channels, excitability of primary sensory neurons, and the molecular basis of pain

Waxman¹,

Cummins²,

Dib‐Hajj³

et al. 1999

Muscle Nerve

184

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Following nerve injury, primary sensory neurons (dorsal root ganglion [DRG] neurons, trigeminal neurons) exhibit a variety of electrophysiological abnormalities, including increased baseline sensitivity and/or hyperexcitability, which can lead to abnormal burst activity that underlies pain, but the molecular basis for these changes has not been fully understood. Over the past several years, it has become clear that nearly a dozen distinct sodium channels are encoded by different genes and that at least six of these (including at least three distinct DRG‐ and trigeminal neuron–specific sodium channels) are expressed in primary sensory neurons. The deployment of different types of sodium channels in different types of DRG neurons endows them with different physiological properties. Dramatic changes in sodium channel expression, including downregulation of the SNS/PN3 and NaN sodium channel genes and upregulation of previously silent type III sodium channel gene, occur in DRG neurons following axonal transection. These changes in sodium channel gene expression are accompanied by a reduction in tetrodotoxin (TTX)‐resistant sodium currents and by the emergence of a TTX‐sensitive sodium current which recovers from inactivation (reprimes) four times more rapidly than the channels in normal DRG neurons. These changes in sodium channel expression poise DRG neurons to fire spontaneously or at inappropriately high frequencies. Changes in sodium channel gene expression also occur in experimental models of inflammatory pain. These observations indicate that abnormal sodium channel expression can contribute to the molecular pathophysiology of pain. They further suggest that selective blockade of particular subtypes of sodium channels may provide new, pharmacological approaches to treatment of disease involving hyperexcitability of primary sensory neurons. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22:1177–1187, 1999

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Sodium channel accumulation in humans with painful neuromas

Cited by 175 publications

References 5 publications

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

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

The molecular basis for electrogenic computation in the brain: you can't step in the same river twice

Sodium channels, excitability of primary sensory neurons, and the molecular basis of pain

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