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Review
. 1999 Jul 6;96(14):7635-9.
doi: 10.1073/pnas.96.14.7635.

Sodium channels and pain

S G Waxman  1 , S Dib-Hajj, T R Cummins, J A Black
Affiliations
Review

Sodium channels and pain

S G Waxman et al. Proc Natl Acad Sci U S A. .

Abstract

Although it is well established that hyperexcitability and/or increased baseline sensitivity of primary sensory neurons can lead to abnormal burst activity associated with pain, the underlying molecular mechanisms are not fully understood. Early studies demonstrated that, after injury to their axons, neurons can display changes in excitability, suggesting increased sodium channel expression, and, in fact, abnormal sodium channel accumulation has been observed at the tips of injured axons. We have used an ensemble of molecular, electrophysiological, and pharmacological techniques to ask: what types of sodium channels underlie hyperexcitability of primary sensory neurons after injury? Our studies demonstrate that multiple sodium channels, with distinct electrophysiological properties, are encoded by distinct mRNAs within small dorsal root ganglion (DRG) neurons, which include nociceptive cells. Moreover, several DRG neuron-specific sodium channels now have been cloned and sequenced. After injury to the axons of DRG neurons, there is a dramatic change in sodium channel expression in these cells, with down-regulation of some sodium channel genes and up-regulation of another, previously silent sodium channel gene. This plasticity in sodium channel gene expression is accompanied by electrophysiological changes that poise these cells to fire spontaneously or at inappropriate high frequencies. Changes in sodium channel gene expression also are observed in experimental models of inflammatory pain. Thus, sodium channel expression in DRG neurons is dynamic, changing significantly after injury. Sodium channels within primary sensory neurons may play an important role in the pathophysiology of pain.

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Figures

Figure 1
Figure 1
Sodium channel α-subunit mRNAs visualized in sections from adult rat DRG by in situ hybridization with subtype-specific antisense riboprobes. mRNAs for α-I, Na6, hNE/PN1, SNS, NaN, and NaG are present at moderate to high levels in DRG neurons. Hybridization signal is not present with sense riboprobes, e.g., for NaG (S). (Bar indicates 100 μm.)
Figure 2
Figure 2
Restriction enzyme profile analysis of Na channel domain 1 reverse transcription–PCR products from DRG. M lanes contain 100-bp ladder marker. Lane 1 contains the amplification product from DRG cDNA. Lanes 2–9 show the result of cutting this DNA with EcoRV, EcoN1, AvaI, SphI, BamHI, AflII, XbaI, and EcoRI, which are specific to subunits α-I, -II, -III, Na6, PN1, SNS, NaG, and NaN, respectively. Reproduced with permission from ref. . (Copyright 1998, National Academy of Sciences, USA).
Figure 3
Figure 3
Transcripts for sodium channel α-III (A) are up-regulated, and transcripts for SNS (B) and NaN (C) are down-regulated, in DRG neurons after transection of their axons within the sciatic nerve. The micrographs (Right) show in situ hybridizations in control DRG, and at 5–7 days postaxotomy. Reverse transcription–PCR (Left) shows products of coamplification of α-III (A) and SNS (B) together with β-actin transcripts in control (C) and axotomized (A) DRG (days postaxotomy indicated above gels in A and B), with computer-enhanced images of amplification products shown below gels. Coamplification of NaN (392 bp) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (606 bp) (C) shows decreased expression of NaN mRNA at 7 days postaxotomy (lanes 2, 4, and 6) compared with controls (lanes 1, 3, and 5). A and B modified from ref. ; C modified from ref. . (Copyright 1998, National Academy of Sciences, USA).
Figure 4
Figure 4
TTX-resistant sodium currents in small DRG neurons are down-regulated after axotomy. (A and B, Left) Whole-cell patch-clamp recordings from representative control (A) and axotomized (B, 6 days postaxotomy) DRG neurons. Note the loss of the TTX-resistant slowly inactivating component of sodium current after axotomy. Steady-state inactivation curves (A and B, Right) show loss of a component characteristic of TTX-resistant currents. (C) Attenuation of TTX-resistant current persists for at least 60 days postaxotomy. (D) Cell capacitance, which provides a measure of cell size, does not change significantly after axotomy (modified from ref. 39).
Figure 5
Figure 5
The kinetics of recovery from inactivation in TTX-sensitive sodium currents are different in axotomized DRG neurons. The graph shows recovery of TTX-sensitive sodium current from inactivation as a function of time in DRG neurons after axonal transection (6 and 22 days postaxotomy, results pooled) compared with uninjured controls. Note the leftward shift in the recovery curve. Modified from ref. .
Figure 6
Figure 6
Reverse transcription–PCR (A), in situ hybridization (B), and patch-clamp recordings (C), showing partial rescue of SNS mRNA and TTX-resistant sodium currents in axotomized DRG neurons after delivery of NGF to the proximal nerve stump. (A) Coamplification of SNS (479 bp) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (666 bp) products in Ringer’s solution-treated axotomized DRG (lanes 1, 2, 5, and 6) and NGF-treated axotomized DRG (lanes 3, 4, 7, and 8). The graph shows the increase in SNS amplification product in NGF-treated DRG. (B) In situ hybridization showing down-regulation of SNS mRNA in DRG after axotomy (axotomy + Ringer’s solution compared with control), and the partial rescue of SNS mRNA by NGF. (C) Representative patch-clamp recordings showing partial rescue of slowly inactivating TTX-resistant sodium currents in axotomized DRG neurons after exposure to NGF. Corresponding steady-state inactivation curves are shown below the recordings. Modified from ref. .
Figure 7
Figure 7
SNS mRNA levels and TTX-resistant sodium currents are increased 4 days after injection of carrageenan into the projection fields of DRG neurons. (Upper) In situ hybridization showing SNS mRNA in carrageenan-injected (A), contralateral control (B), and naive (C) DRG. Patch-clamp recordings (D–F) do not reveal any change in voltage dependence of activation or steady-state inactivation of TTX-resistant sodium currents after carrageenan injection, but demonstrate an increase in TTX-resistant current amplitude (D) and density. Modified from ref. .
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References

    1. Ochoa J, Torebjork H E. Brain. 1980;103:835–854. - PubMed
    1. Nordin M, Nystrom B, Wallin U, Hagbarth K-E. Pain. 1984;20:231–245. - PubMed
    1. Devor M. In: Textbook of Pain. 2nd Ed. Wall P D, Melzack R, editors. Edinburgh: Churchill Livingstone; 1994. pp. 79–101.
    1. Eccles J C, Libet B, Young R R. J Physiol (London) 1958;143:11–40. - PMC - PubMed
    1. Kuno M, Llinas R. J Physiol (London) 1970;210:807–821. - PMC - PubMed

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