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Regulating excitability of peripheral afferents: emerging ion channel targets

Nature Neuroscience volume 17, pages 153–163 (2014)Cite this article

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Abstract

The transmission and processing of pain signals relies critically on the activities of ion channels that are expressed in afferent pain fibers. This includes voltage-gated channels, as well as background (or leak) channels that collectively regulate resting membrane potential and action potential firing properties. Dysregulated ion channel expression in response to nerve injury and inflammation results in enhanced neuronal excitability that underlies chronic neuropathic and inflammatory pain. Pharmacological modulators of ion channels, particularly those that target channels on peripheral neurons, are being pursued as possible analgesics. Over the past few years, a number of different types of ion channels have been implicated in afferent pain signaling. Here we give an overview of recent advances on sodium, calcium, potassium and chloride channels that are emerging as especially attractive targets for the treatment of pain.

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Figure 1: Key ion channels in the primary afferent pain pathway.
Figure 2: The G856D mutation in NaV1.7 that segregates with disease in a family with painful neuropathy increases neuronal excitability.
Figure 3: Atomic-level structural modeling and thermodynamic analyses predict that the S241T mutation should increase sensitivity of the NaV1.7 channel to carbamazepine.
Figure 4: Examples of mechanisms of nerve injury–induced inhibition of potassium channel expression.
Figure 5: Possible mechanisms by which T-type channels contribute to afferent fiber activity.

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Acknowledgements

We thank C. Midgley for editorial assistance. G.W.Z. is supported by a Canada Research Chair award, an Alberta Innovates – Health Solutions Scientist award and grants from the Canadian Institutes of Health Research. S.G.W. is supported by the Bridget M. Flaherty Professorship in Neurology, Neurobiology and Pharmacology at Yale and is supported by grants from the Rehabilitation Research Service and Biomedical Laboratory Research Service, US Department of Veterans Affairs.

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  1. Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA

    Stephen G Waxman

  2. Veterans Affairs Medical Center, West Haven, Connecticut, USA

    Stephen G Waxman

  3. Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada

    Gerald W Zamponi

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Waxman, S., Zamponi, G. Regulating excitability of peripheral afferents: emerging ion channel targets. Nat Neurosci 17, 153–163 (2014). https://doi.org/10.1038/nn.3602

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