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The physiological function of different voltage-gated sodium channels in pain

Abstract

Evidence from human genetic pain disorders shows that voltage-gated sodium channel α-subtypes Nav1.7, Nav1.8 and Nav1.9 are important in the peripheral signalling of pain. Nav1.7 is of particular interest because individuals with Nav1.7 loss-of-function mutations are congenitally insensitive to acute and chronic pain, and there is considerable hope that phenocopying these effects with a pharmacological antagonist will produce a new class of analgesic drug. However, studies in these rare individuals do not reveal how and where voltage-gated sodium channels contribute to pain signalling, which is of critical importance for drug development. More than a decade of research utilizing rodent genetic models and pharmacological tools to study voltage-gated sodium channels in pain has begun to unravel the role of different subtypes. Here, we review the contribution of individual channel subtypes in three key physiological processes necessary for transmission of sensory information to the CNS: transduction of stimuli at peripheral nerve terminals, axonal transmission of action potentials and neurotransmitter release from central terminals. These data suggest that drugs seeking to recapitulate the analgesic effects of loss of function of Nav1.7 will need to be brain-penetrant — which most of those developed to date are not.

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Fig. 1: Summary of the contribution of different Navs to neuronal activity in nociceptive neurons innervating somatic and visceral tissue.

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Acknowledgements

The authors thank E. Stevens for useful comments on the manuscript.

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G.G. and S.B.M. contributed equally to this work.

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Glossary

Paroxysmal extreme pain disorder

A type of peripheral neuropathy characterized by skin redness, warmth and attacks of severe pain in various parts of the body.

Pruritus

Severe itching of the skin.

Brugada syndrome

A genetic disorder that can cause a dangerous irregular heartbeat.

Microneurography

A neurophysiological technique for recording electrical activity from peripheral nerve fibres.

Hyperalgesia

Increased pain from a stimulus that normally provokes pain.

Neuroma

A disorganized growth of nerve fibres at the site of nerve injury.

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Goodwin, G., McMahon, S.B. The physiological function of different voltage-gated sodium channels in pain. Nat Rev Neurosci 22, 263–274 (2021). https://doi.org/10.1038/s41583-021-00444-w

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