The role of Nav1.9 channel in the development of neuropathic orofacial pain associated with trigeminal neuralgia

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Abstract

Background

Trigeminal neuralgia is accompanied by severe mechanical, thermal and chemical hypersensitivity of the orofacial area innervated by neurons of trigeminal ganglion (TG). We examined the role of the voltage-gated sodium channel subtype Na _v1.9 in the development of trigeminal neuralgia.

Results

We found that Na _v1.9 is required for the development of both thermal and mechanical hypersensitivity induced by constriction of the infraorbital nerve (CION). The CION model does not induce change on Na _v1.9 mRNA expression in the ipsilateral TG neurons when evaluated 9 days after surgery.

Conclusions

These results demonstrate that Na _v1.9 channels play a critical role in the development of orofacial neuropathic pain. New routes for the treatment of orofacial neuropathic pain focussing on regulation of the voltage-gated Na _v1.9 sodium channel activity should be investigated.

Related collections

Most cited references 35

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A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons.

A Akopian, L Sivilotti, J Wood (1996)

Dorsal root ganglion sensory neurons associated with C-fibres, many of which are activated by tissue-damage, express an unusual voltage-gated sodium channel that is resistant to tetrodotoxin. We report here that we have identified a 1,957 amino-acid sodium channel in these cells that shows 65% identity with the rat cardiac tetrodotoxin-insensitive sodium channel, and is not expressed in other peripheral and central neurons, glia or non-neuronal tissues. In situ hybridization shows that the channel is expressed only by small-diameter sensory neurons in neonatal and adult dorsal root and trigeminal ganglia. The channel is resistant to tetrodotoxin when expressed in Xenopus oocytes. The electrophysiological and pharmacological properties of the expressed channel are similar to those described for the small-diameter sensory neuron tetrodotoxin-resistant sodium channels. As some noxious input into the spinal cord is resistant to tetrodotoxin, block of expression or function of such a C-fibre-restricted sodium channel may have a selective analgesic effect.

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Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat's infraorbital nerve.

BP Vos, AM Strassman, RJ Maciewicz (1994)

Video recordings of free behavior and responses to mechanical facial stimulation were analyzed to assess whether chronic constriction injury (CCI) to the rat's infraorbital nerve (IoN) results in behavioral alterations indicative of neuropathic pain. A unilateral CCI was produced by placing loose chromic gut ligatures around the IoN. After CCI to the IoN, rats exhibited changes in both non-evoked and evoked behavior. Behavioral changes developed in two phases. Early after CCI (postoperative days 1-15), rats showed increased face-grooming activity with face-wash strokes directed to the injured nerve territory, while the responsiveness to stimulation of this area was decreased. Later after CCI (postoperative days 15-130), the prevalence of asymmetric face grooming was reduced but remained significantly increased compared to control rats. The early hyporesponsiveness was abruptly replaced by an extreme hyperresponsiveness: all stimulus intensities applied to the injured nerve territory evoked the "maximal" response (brisk head withdrawal, avoidance behavior plus directed face grooming). This response was never observed in control rats. Concurrently, IoN ligation rats showed a limited increase in the responsiveness to stimulation of the contralateral IoN territory, and around postoperative days 30-40 the responsiveness to stimulation of facial areas outside the IoN territories also increased. The hyperresponsiveness to stimulation of the ligated IoN territory slightly decreased from 60 d postoperative. Throughout the study, IoN ligation rats showed decreased exploratory behavior, displayed more freezing-like behavior, had a slower body weight gain, and a higher defecation rate, compared to control rats. The behavioral alterations observed after CCI to the IoN are indicative of severe sensory disturbances within the territory of the injured nerve: mechanical allodynia develops after a period of relative hypo-/anesthesia during which behavioral signs of recurrent spontaneous, aversive (possibly painful) sensations (paresthesias/dysesthesias) are maximal.

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A de novo gain-of-function mutation in SCN11A causes loss of pain perception.

Enrico Leipold, Lutz Liebmann, G. Korenke … (2013)

The sensation of pain protects the body from serious injury. Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Nav1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors, which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system. Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. The gain-of-function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception.

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Author and article information

Contributors

Ana Paula Luiz: +44 207 679 0793 , a.luiz@ucl.ac.uk

Olga Kopach: o.kopach@ucl.ac.uk

Sonia Santana-Varela: s.santana@ucl.ac.uk

John N. Wood: j.wood@ucl.ac.uk

Journal

Journal ID (nlm-ta): Mol Pain

Journal ID (iso-abbrev): Mol Pain

Title: Molecular Pain

Publisher: BioMed Central (London )

ISSN (Electronic): 1744-8069

Publication date (Electronic): 25 November 2015

Publication date PMC-release: 25 November 2015

Publication date Collection: 2015

Volume: 11

Electronic Location Identifier: 72

Affiliations

[ ]Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower St, London, WC1E 6BT UK

[ ]Department of Molecular Medicine and Biopharmaceutical Sciences, College of Medicine, Seoul National University, Seoul, South Korea

Article

Publisher ID: 76

DOI: 10.1186/s12990-015-0076-4

PMC ID: 4658751

PubMed ID: 26607325

SO-VID: b116a9d2-88cd-4cdd-a3f7-246eb8fa2ed7

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 7 May 2015

Date accepted : 12 November 2015

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: nav1.9 sodium channels,trigeminal ganglion (tg) neurons,constriction of the infraorbital nerve,trigeminal neuralgia,neuropathic pain

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: nav1.9 sodium channels, trigeminal ganglion (tg) neurons, constriction of the infraorbital nerve, trigeminal neuralgia, neuropathic pain