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Increased peripheral nerve excitability and local NaV1.8 mRNA up-regulation in painful neuropathy.

Thakor DK, Lin A, Matsuka Y, Meyer EM, Ruangsri S, Nishimura I, Spigelman I - Mol Pain (2009)

Bottom Line: Furthermore, mRNA levels of NaV1.3, NaV1.5, NaV1.6, NaV1.7, and NaV1.9 were not significantly different between ipsilateral and contralateral nerves.Cuff entrapment injury resulted in significantly elevated axonal excitability and increased NaV1.8 immunoreactivity in rat sciatic nerves.The concomitant axonal accumulation of NaV1.8 mRNA may play a role in the pathogenesis of this model of neuropathic pain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, CA 90095-1668, USA. dthakor@ucla.edu

ABSTRACT

Background: Neuropathic pain caused by peripheral nerve injury is a chronic disorder that represents a significant clinical challenge because the pathological mechanisms have not been fully elucidated. Several studies have suggested the involvement of various sodium channels, including tetrodotoxin-resistant NaV1.8, in affected dorsal root ganglion (DRG) neurons. We have hypothesized that altered local expression of NaV1.8 in the peripheral axons of DRG neurons could facilitate nociceptive signal generation and propagation after neuropathic injury.

Results: After unilateral sciatic nerve entrapment injury in rats, compound action potential amplitudes were increased in both myelinated and unmyelinated fibers of the ipsilateral sciatic nerve. Tetrodotoxin resistance of both fiber populations and sciatic nerve NaV1.8 immunoreactivity were also increased. Further analysis of NaV1.8 distribution revealed that immunoreactivity and mRNA levels were decreased and unaffected, respectively, in the ipsilateral L4 and L5 DRG; however sciatic nerve NaV1.8 mRNA showed nearly an 11-fold ipsilateral increase. Nav1.8 mRNA observed in the sciatic nerve was likely of axonal origin since it was not detected in non-neuronal cells cultured from nerve tissue. Absence of changes in NaV1.8 mRNA polyadenylation suggests that increased mRNA stability was not responsible for the selective peripheral mRNA increase. Furthermore, mRNA levels of NaV1.3, NaV1.5, NaV1.6, NaV1.7, and NaV1.9 were not significantly different between ipsilateral and contralateral nerves. We therefore propose that selective NaV1.8 mRNA axonal transport and local up-regulation could contribute to the hyperexcitability of peripheral nerves in some neuropathic pain states.

Conclusion: Cuff entrapment injury resulted in significantly elevated axonal excitability and increased NaV1.8 immunoreactivity in rat sciatic nerves. The concomitant axonal accumulation of NaV1.8 mRNA may play a role in the pathogenesis of this model of neuropathic pain.

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Increased TTX-resistance of the sciatic nerve after SNE. A: TTX-resistance of the A-fiber sciatic nerve compound action potential (CAP) ipsilateral to SNE (n = 8) compared to contralateral, naïve and sham surgery nerves (n = 8). CAP response is expressed as a % of recorded amplitude before TTX administration. A-fiber CAP stimulus was 0.1 mA, 0.1 ms throughout. B: Changes in TTX-resistance of the C-fiber sciatic nerve CAP after SNE. C-fiber CAP stimulus was 10 mA, 0.5 ms throughout. * indicates significant difference from control nerve sensitivity to TTX (p < 0.05, two-way ANOVA, Tukey post-hoc). Tissue was harvested 2 weeks after SNE or sham surgery.
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Figure 2: Increased TTX-resistance of the sciatic nerve after SNE. A: TTX-resistance of the A-fiber sciatic nerve compound action potential (CAP) ipsilateral to SNE (n = 8) compared to contralateral, naïve and sham surgery nerves (n = 8). CAP response is expressed as a % of recorded amplitude before TTX administration. A-fiber CAP stimulus was 0.1 mA, 0.1 ms throughout. B: Changes in TTX-resistance of the C-fiber sciatic nerve CAP after SNE. C-fiber CAP stimulus was 10 mA, 0.5 ms throughout. * indicates significant difference from control nerve sensitivity to TTX (p < 0.05, two-way ANOVA, Tukey post-hoc). Tissue was harvested 2 weeks after SNE or sham surgery.

Mentions: Concentration-dependent decreases in CAP amplitude were detected within 30 sec after TTX (0.1–1 μM) was applied in the recording chamber (p < 0.05, two-way ANOVA with Tukey post-hoc) and measurements were obtained after 20–25 min to ensure a full drug response. The C-and A-fiber CAPs in both injured and uninjured nerves were blocked completely in the presence of 1 μM TTX (not shown). At lower concentrations, the TTX-resistance of both the A-fiber and C-fiber CAPs was significantly increased in nerves ipsilateral to SNE (p < 0.05, two-way ANOVA with Tukey post-hoc) (Fig. 2A, B).


Increased peripheral nerve excitability and local NaV1.8 mRNA up-regulation in painful neuropathy.

Thakor DK, Lin A, Matsuka Y, Meyer EM, Ruangsri S, Nishimura I, Spigelman I - Mol Pain (2009)

Increased TTX-resistance of the sciatic nerve after SNE. A: TTX-resistance of the A-fiber sciatic nerve compound action potential (CAP) ipsilateral to SNE (n = 8) compared to contralateral, naïve and sham surgery nerves (n = 8). CAP response is expressed as a % of recorded amplitude before TTX administration. A-fiber CAP stimulus was 0.1 mA, 0.1 ms throughout. B: Changes in TTX-resistance of the C-fiber sciatic nerve CAP after SNE. C-fiber CAP stimulus was 10 mA, 0.5 ms throughout. * indicates significant difference from control nerve sensitivity to TTX (p < 0.05, two-way ANOVA, Tukey post-hoc). Tissue was harvested 2 weeks after SNE or sham surgery.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2667430&req=5

Figure 2: Increased TTX-resistance of the sciatic nerve after SNE. A: TTX-resistance of the A-fiber sciatic nerve compound action potential (CAP) ipsilateral to SNE (n = 8) compared to contralateral, naïve and sham surgery nerves (n = 8). CAP response is expressed as a % of recorded amplitude before TTX administration. A-fiber CAP stimulus was 0.1 mA, 0.1 ms throughout. B: Changes in TTX-resistance of the C-fiber sciatic nerve CAP after SNE. C-fiber CAP stimulus was 10 mA, 0.5 ms throughout. * indicates significant difference from control nerve sensitivity to TTX (p < 0.05, two-way ANOVA, Tukey post-hoc). Tissue was harvested 2 weeks after SNE or sham surgery.
Mentions: Concentration-dependent decreases in CAP amplitude were detected within 30 sec after TTX (0.1–1 μM) was applied in the recording chamber (p < 0.05, two-way ANOVA with Tukey post-hoc) and measurements were obtained after 20–25 min to ensure a full drug response. The C-and A-fiber CAPs in both injured and uninjured nerves were blocked completely in the presence of 1 μM TTX (not shown). At lower concentrations, the TTX-resistance of both the A-fiber and C-fiber CAPs was significantly increased in nerves ipsilateral to SNE (p < 0.05, two-way ANOVA with Tukey post-hoc) (Fig. 2A, B).

Bottom Line: Furthermore, mRNA levels of NaV1.3, NaV1.5, NaV1.6, NaV1.7, and NaV1.9 were not significantly different between ipsilateral and contralateral nerves.Cuff entrapment injury resulted in significantly elevated axonal excitability and increased NaV1.8 immunoreactivity in rat sciatic nerves.The concomitant axonal accumulation of NaV1.8 mRNA may play a role in the pathogenesis of this model of neuropathic pain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, CA 90095-1668, USA. dthakor@ucla.edu

ABSTRACT

Background: Neuropathic pain caused by peripheral nerve injury is a chronic disorder that represents a significant clinical challenge because the pathological mechanisms have not been fully elucidated. Several studies have suggested the involvement of various sodium channels, including tetrodotoxin-resistant NaV1.8, in affected dorsal root ganglion (DRG) neurons. We have hypothesized that altered local expression of NaV1.8 in the peripheral axons of DRG neurons could facilitate nociceptive signal generation and propagation after neuropathic injury.

Results: After unilateral sciatic nerve entrapment injury in rats, compound action potential amplitudes were increased in both myelinated and unmyelinated fibers of the ipsilateral sciatic nerve. Tetrodotoxin resistance of both fiber populations and sciatic nerve NaV1.8 immunoreactivity were also increased. Further analysis of NaV1.8 distribution revealed that immunoreactivity and mRNA levels were decreased and unaffected, respectively, in the ipsilateral L4 and L5 DRG; however sciatic nerve NaV1.8 mRNA showed nearly an 11-fold ipsilateral increase. Nav1.8 mRNA observed in the sciatic nerve was likely of axonal origin since it was not detected in non-neuronal cells cultured from nerve tissue. Absence of changes in NaV1.8 mRNA polyadenylation suggests that increased mRNA stability was not responsible for the selective peripheral mRNA increase. Furthermore, mRNA levels of NaV1.3, NaV1.5, NaV1.6, NaV1.7, and NaV1.9 were not significantly different between ipsilateral and contralateral nerves. We therefore propose that selective NaV1.8 mRNA axonal transport and local up-regulation could contribute to the hyperexcitability of peripheral nerves in some neuropathic pain states.

Conclusion: Cuff entrapment injury resulted in significantly elevated axonal excitability and increased NaV1.8 immunoreactivity in rat sciatic nerves. The concomitant axonal accumulation of NaV1.8 mRNA may play a role in the pathogenesis of this model of neuropathic pain.

Show MeSH
Related in: MedlinePlus