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Acute pain signaling has a key protective role and is highly evolutionarily conserved. Chronic pain, however, is maladaptive, occurring as a consequence of injury and disease, and is associated with sensitization of the somatosensory nervous system. Primary sensory neurons are involved in both of these processes, and the recent advances in understanding sensory transduction and human genetics are the focus of this review. Voltage-gated sodium channels (VGSCs) are important determinants of sensory neuron excitability: they are essential for the initial transduction of sensory stimuli, the electrogenesis of the action potential, and neurotransmitter release from sensory neuron terminals. Nav1.1, Nav1.6, Nav1.7, Nav1.8, and Nav1.9 are all expressed by adult sensory neurons. The biophysical characteristics of these channels, as well as their unique expression patterns within subtypes of sensory neurons, define their functional role in pain signaling. Changes in the expression of VGSCs, as well as posttranslational modifications, contribute to the sensitization of sensory neurons in chronic pain states. Furthermore, gene variants in Nav1.7, Nav1.8, and Nav1.9 have now been linked to human Mendelian pain disorders and more recently to common pain disorders such as small-fiber neuropathy. Chronic pain affects one in five of the general population. Given the poor efficacy of current analgesics, the selective expression of particular VGSCs in sensory neurons makes these attractive targets for drug discovery. The increasing availability of gene sequencing, combined with structural modeling and electrophysiological analysis of gene variants, also provides the opportunity to better target existing therapies in a personalized manner.

Original publication

DOI

10.1152/physrev.00052.2017

Type

Journal article

Journal

Physiological reviews

Publication Date

04/2019

Volume

99

Pages

1079 - 1151

Addresses

Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford , United Kingdom ; Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine , New Haven, Connecticut ; and Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut.

Keywords

Animals, Humans, Analgesics, Pain Threshold, Signal Transduction, Drug Design, Sensory Receptor Cells, Chronic Pain, Voltage-Gated Sodium Channel Blockers, Voltage-Gated Sodium Channels