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Sensory Nerves pp 519-561 | Cite as

The Pharmacology of Voltage-Gated Sodium Channels in Sensory Neurones

  • Reginald J. Docherty
  • Clare E. Farmer
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 194)

Abstract

Voltage-gated sodium channels (VGSCs) are vital for the normal functioning of most excitable cells. At least nine distinct functional subtypes of VGSCs are recognized, corresponding to nine genes for their pore-forming α-subunits. These have different developmental expression patterns, different tissue distributions in the adult and are differentially regulated at the cellular level by receptor-coupled cell signalling systems. Unsurprisingly, VGSC blockers are found to be useful as drugs in diverse clinical applications where excessive excitability of tissue leads to pathological dysfunction, e.g. epilepsy or cardiac tachyarrhythmias. The effects of most clinically useful VGSC blockers are use-dependent, i.e. their efficacy depends on channel activity. In addition, many natural toxins have been discovered that interact with VGSCs in complex ways and they have been used as experimental probes to study the structure and function of the channels and to better understand how drugs interact with the channels. Here we have attempted to summarize the properties of VGSCs in sensory neurones, discuss how they are regulated by cell signalling systems and we have considered briefly current concepts of their physiological function. We discuss in detail how drugs and toxins interact with archetypal VGSCs and where possible consider how they act on VGSCs in peripheral sensory neurones. Increasingly, drugs that block VGSCs are being used as systemic analgesic agents in chronic pain syndromes, but the full potential for VGSC blockers in this indication is yet to be realized and other applications in sensory dysfunction are also possible. Drugs targeting VGSC subtypes in sensory neurones are likely to provide novel systemic analgesics that are tissue-specific and perhaps even disease-specific, providing much-needed novel therapeutic approaches for the relief of chronic pain.

Keywords

Voltage-gated sodium channel Local anaesthetic Anticonvulsant Antiarrhythmic Tetrodotoxin Pain Hyperalgesia Analgesic 

Abbreviations

BTX

Batrachotoxin

DRG

Dorsal root ganglion

IFM

Isoleucine, phenylalanine and methionine

MAPK

Mitogen-activated protein kinase

PKA

Protein kinase A

PKC

Protein kinase C

STX

Saxitoxin

TTX

Tetrodotoxin

TTXR

Tetrodotoxin resistant

TTXS

Tetrodotoxin sensitive

VGSC

Voltage-gated sodium channel

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Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Reginald J. Docherty
    • 1
  • Clare E. Farmer
    • 1
  1. 1.Neurorestoration Group, Wolfson CARDKing’s College LondonLondonUK

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