Faculty Collaboration Database

A gain-of-function voltage-gated sodium channel 1.8 mutation drives intense hyperexcitability of A- and C-fiber neurons. Pain 2014 May;155(5):896-905

Date

01/23/2014

Pubmed ID

24447515

Pubmed Central ID

PMC3989381

DOI

10.1016/j.pain.2014.01.012

Scopus ID

2-s2.0-84898597785 (requires institutional sign-in at Scopus site)   33 Citations

Abstract

Therapeutic use of general sodium channel blockers, such as lidocaine, can substantially reduce the enhanced activity in sensory neurons that accompanies chronic pain after nerve or tissue injury. However, because these general blockers have significant side effects, there is great interest in developing inhibitors that specifically target subtypes of sodium channels. Moreover, some idiopathic small-fiber neuropathies are driven by gain-of-function mutations in specific sodium channel subtypes. In the current study, we focus on one subtype, the voltage-gated sodium channel 1.8 (Nav1.8). Nav1.8 is preferentially expressed in nociceptors, and gain-of-function mutations in Nav1.8 result in painful mechanical hypersensitivity in humans. Here, we used the recently developed gain-of-function Nav1.8 transgenic mouse strain, Possum, to investigate Nav1.8-mediated peripheral afferent hyperexcitability. This gain-of-function mutation resulted in markedly increased mechanically evoked action potential firing in subclasses of Aβ, Aδ, and C fibers. Moreover, mechanical stimuli initiated bursts of action potential firing in specific subpopulations that continued for minutes after removal of the force and were not susceptible to conduction failure. Surprisingly, despite the intense afferent firing, the behavioral effects of the Nav1.8 mutation were quite modest, as only frankly noxious stimuli elicited enhanced pain behavior. These data demonstrate that a Nav1.8 gain-of-function point mutation contributes to intense hyperexcitability along the afferent axon within distinct sensory neuron subtypes.

Author List

Garrison SR, Weyer AD, Barabas ME, Beutler BA, Stucky CL

Author

Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Action Potentials
Animals
Axons
Behavior, Animal
Calcium
Mice
Mice, Transgenic
NAV1.8 Voltage-Gated Sodium Channel
Nerve Fibers, Myelinated
Nerve Fibers, Unmyelinated
Pain Measurement
Pain Threshold
Patch-Clamp Techniques
Physical Stimulation
Point Mutation