Sodium channels

The Peripheral Neuropathy Solution

Dr. Labrum Peripheral Neuropathy Program

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Sodium (Na1) channels are critical to the physiology of excitable membranes. There are significant alterations in the expression of Na1 channels in the cell bodies and the terminal neuroma of peripheral nerves following nerve injury. Such accumulation of Na channels in the neuroma of cut sensory axons45 are thought to generate ectopic discharge (Figure 1.5).46

There are many different and distinct voltage-gated Na1 channels, of which at least six are expressed by primary afferent neurons within the DRG.47 These can be defined by their sensitivity to TTX. In the DRG, TTX-sensitive channels (TTX-s) are expressed predominantly by A-fibers. In contrast, TTX-resistant (TTX-r) channels are expressed by a subset of primary afferent neurons specifically in the smaller C-fibers associated with

Bursting firing

Irregular spontaneous firing

Figure 1.4 Patterns of spontaneous ectopic discharge recorded from sensory neurons ending in a neuroma. Fine axon bundles were microdissected from an injured nerve and placed on a recording electrode (R). Spontaneously active fibers fire tonically (1), in bursts (2), or irregularly (3). Intracellular recording from a dorsal root ganglion neuron with ectopic burst discharge (asterisks, spike height is truncated). One burst is shown in detail below. Bursts are triggered when ongoing membrane potential oscillations reach threshold and are maintained by postspike depolarizing after potentials (DAP). The burst initiates a hyperpolarizing shift which stops firing and resets the oscillations. Reprinted from Devor, Melzack and Wall's Textbook of Pain. 2005, 5th Edition © 2005 Elsevier Ltd,38 adapted from Amir and Devor 1992.39 Used with permission from The American Physiological Society and Elsevier.

Sprouting of sympathetic fibers

Sprouting of sympathetic fibers

C-fiber

Nociceptive terminals

C-fiber

Nociceptive terminals

Ectopic

Ectopic

Figure 1.5 Alterations in Na1 and Ca21 channel subunits in the peripheral nervous system (PNS) following nerve injury. There is an increase in the expression of tetrodotoxin sensitive Nav1.3 channels and the calcium channel «28-1 (Cava28-1) subunits in dorsal root ganglion (DRG) neuron cell bodies. The tetrodotoxin-resistant Na1 channel subunits Nav1.8 and Nav1.9 decrease in the DRG and are also redistributed from the DRG neuron cell bodies to peripheral axons at the site of injury. Sprouting of sympathetic nerve fibers in the DRG also act to sensitize peripheral afferents. These changes are thought to result in spontaneous ectopic discharges and lower the threshold for mechanical activation that leads to hypersensitivity.

nociception.48 Following peripheral nerve injury, there is a reorganization of ion channel expression in DRG neu-rons.36 Some sodium channels subtypes are diminished, whilst others appear de novo and others are translocated to different parts of the neuron. For example, there is an up-regulation of the TTX-s channels Nav1.3 (not normally expressed by DRG cells) and Nav1.7, and a down-regulation of the TTX-r channels Nav1.8 and Nav1.9. As Nav1.8 and Nav1.9 produce slowly inactivating currents, their decreased expression may lead to a hyperpolarizing shift in resting potential, increasing the fraction of TTX-s channels available for activation.47'49 Electrophysiological studies demonstrate a reduced density of TTX-r currents and a shift in the voltage dependence of activation to a more negative potential in the following nerve injury.49 In contrast, up-regulation of Nav1.3 results in a switch in the properties of the TTX-s currents in DRG neurons, with the emergence of a rapidly repriming current, which could sustain frequent ectopic discharges and lead to hyper-excitability in the cell.50 In support of this, TTX produces dose-dependent inhibition of ectopic activity51 and reduced mechanical hypersensitivity in the spinal nerve transection (SNT) model.52 In partial nerve injuries, the intact afferent neurons show little or no change in the expression of Nav1.8, although there is a redistribution of these channels from their cell bodies in the DRG to their axons,53 which may explain the neuroma hypersensitivity. These findings were corroborated in immunohisto-chemical studies of tissue taken from patients suffering from neuropathic pain following traumatic brachial plexus avulsion54 and in human sensory nerves localized close to the injury site and within the neuroma.55

A Na channel subunit that has received more attention in recent years is the Nav1.7 channel. Nav1.7 is expressed, almost exclusively, in DRG, particularly in small C-fiber nociceptors and to a lesser extent in medium-sized A8 and large Ap cells.56 The Nav1.7 channel underlies a fast TTX-s current with slow repriming kinetics and slow inactivation. Significantly, the Nav1.7 channel has been localized to sensory endings, such that both its distribution and physiology may predispose it to a major role in transmitting painful stimuli. A mutation in the human gene encoding Nav1.7 resulting in sensory neuron hyperexcitability is thought to be associated with the development of neuropathic pain in primary ery-thermalgia.57'58 However, experimentally the role for Nav1.7 in neuropathic pain is unclear as mice lacking this channel develop signs of neuropathic pain as normal.59

The mechanism contributing to the changes in Na1 channel expression in peripheral nerve injury is unclear, but the influence of growth factors appears to be a crucial factor. For example, in the absence of nerve growth factor (NGF), DRG neurons in vitro increase Nav1.3 expression and decrease Nav1.8 expression.60 NGF is a member of the neurotrophin family of polypeptides, which are produced by peripheral target tissue during embryonic development, are required for peripheral sensory neurons for survival and can influence the morphology, excitability, and synaptic plasticity of sensory neurons in adulthood.61 Additionally, glial-derived neurotrophic factor (GDNF), a member of a second family of growth factors, normalizes Nav1.3 expression, reduces ectopic discharge in A-fibers, and reduces hypersensitivity62 when delivered to the injured nerve. Nav1.9 expression is similarly reliant on GDNF.

Therapeutic agents that exhibit use-dependent block of sodium channels show efficacy against painful peripheral neuropathy in the clinic. Systemic administration of lidocaine and other sodium-channel blockers relieves painful symptoms of postherpetic neuralgia, painful diabetic neuropathy, idiopathic trigeminal neuralgia, and other conditions.63 Topical lidocaine also relieves pain in postherpetic neuralgia.64 Sodium channel blockade is also a likely mechanism through which at least some drugs which also have efficacy in epilepsy (e.g. phenytoin and carbamazepine) might suppress neuropathic pain and the well-established efficacy of tricyclic antidepressants (TCA) may be due, at least in part, to their ability to block sodium channels.65

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