μO-conotoxin MrVIB selectively blocks NaV1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits

J. Ekberg, A. Jayamanne, C. W. Vaughan, S. Aslan, Linda Thomas, J. Mould, Roger Drinkwater, M. D. Baker, B. Abrahamsen, J. N. Wood, David J. Adams, M. J. Christie, Richard J. Lewis

Research output: Contribution to journalArticleResearchpeer-review

147 Citations (Scopus)

Abstract

The tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na V1.8 is expressed predominantly by damage-sensing primary afferent nerves and is important for the development and maintenance of persistent pain states. Here we demonstrate that μO-conotoxin MrVIB from Conus marmoreus displays substantial selectivity for NaV1.9 and inhibits pain behavior in models of persistent pain. In rat sensory neurons, submicromolar concentrations of MrVIB blocked tetrodotoxin-resistant current characteristic of NaV1.8 but not NaV1.9 or tetrodotoxin-sensitive VGSC currents. MrVIB blocked human NaV1.8 expressed in Xenopus oocytes with selectivity at least 10-fold greater than other VGSCs. In neuropathic and chronic inflammatory pain models, allodynia and hyperalgesia were both reduced by intrathecal infusion of MrVIB (0.03-3 nmol), whereas motor side effects occurred only at 30-fold higher doses. In contrast, the nonselective VGSC blocker lignocaine displayed no selectivity for allodynia and hyperalgesia versus motor side effects. The actions of MrVIB reveal that VGSC antagonists displaying selectivity toward NaV1.8 can alleviate chronic pain behavior with a greater therapeutic index than nonselective antagonists.

Original languageEnglish
Pages (from-to)17030-17035
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number45
DOIs
Publication statusPublished - 7 Nov 2006
Externally publishedYes

Fingerprint

Sodium Channels
Hyperalgesia
Sensory Receptor Cells
Chronic Pain
Voltage-Gated Sodium Channel Blockers
Tetrodotoxin
Voltage-Gated Sodium Channels
Pain
Xenopus
Lidocaine
Oocytes
Maintenance
conotoxin MrVIB
Therapeutics

Cite this

Ekberg, J. ; Jayamanne, A. ; Vaughan, C. W. ; Aslan, S. ; Thomas, Linda ; Mould, J. ; Drinkwater, Roger ; Baker, M. D. ; Abrahamsen, B. ; Wood, J. N. ; Adams, David J. ; Christie, M. J. ; Lewis, Richard J. / μO-conotoxin MrVIB selectively blocks NaV1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 45. pp. 17030-17035.
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title = "μO-conotoxin MrVIB selectively blocks NaV1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits",
abstract = "The tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na V1.8 is expressed predominantly by damage-sensing primary afferent nerves and is important for the development and maintenance of persistent pain states. Here we demonstrate that μO-conotoxin MrVIB from Conus marmoreus displays substantial selectivity for NaV1.9 and inhibits pain behavior in models of persistent pain. In rat sensory neurons, submicromolar concentrations of MrVIB blocked tetrodotoxin-resistant current characteristic of NaV1.8 but not NaV1.9 or tetrodotoxin-sensitive VGSC currents. MrVIB blocked human NaV1.8 expressed in Xenopus oocytes with selectivity at least 10-fold greater than other VGSCs. In neuropathic and chronic inflammatory pain models, allodynia and hyperalgesia were both reduced by intrathecal infusion of MrVIB (0.03-3 nmol), whereas motor side effects occurred only at 30-fold higher doses. In contrast, the nonselective VGSC blocker lignocaine displayed no selectivity for allodynia and hyperalgesia versus motor side effects. The actions of MrVIB reveal that VGSC antagonists displaying selectivity toward NaV1.8 can alleviate chronic pain behavior with a greater therapeutic index than nonselective antagonists.",
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Ekberg, J, Jayamanne, A, Vaughan, CW, Aslan, S, Thomas, L, Mould, J, Drinkwater, R, Baker, MD, Abrahamsen, B, Wood, JN, Adams, DJ, Christie, MJ & Lewis, RJ 2006, 'μO-conotoxin MrVIB selectively blocks NaV1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits' Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 45, pp. 17030-17035. https://doi.org/10.1073/pnas.0601819103

μO-conotoxin MrVIB selectively blocks NaV1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits. / Ekberg, J.; Jayamanne, A.; Vaughan, C. W.; Aslan, S.; Thomas, Linda; Mould, J.; Drinkwater, Roger; Baker, M. D.; Abrahamsen, B.; Wood, J. N.; Adams, David J.; Christie, M. J.; Lewis, Richard J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 45, 07.11.2006, p. 17030-17035.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - μO-conotoxin MrVIB selectively blocks NaV1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits

AU - Ekberg, J.

AU - Jayamanne, A.

AU - Vaughan, C. W.

AU - Aslan, S.

AU - Thomas, Linda

AU - Mould, J.

AU - Drinkwater, Roger

AU - Baker, M. D.

AU - Abrahamsen, B.

AU - Wood, J. N.

AU - Adams, David J.

AU - Christie, M. J.

AU - Lewis, Richard J.

PY - 2006/11/7

Y1 - 2006/11/7

N2 - The tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na V1.8 is expressed predominantly by damage-sensing primary afferent nerves and is important for the development and maintenance of persistent pain states. Here we demonstrate that μO-conotoxin MrVIB from Conus marmoreus displays substantial selectivity for NaV1.9 and inhibits pain behavior in models of persistent pain. In rat sensory neurons, submicromolar concentrations of MrVIB blocked tetrodotoxin-resistant current characteristic of NaV1.8 but not NaV1.9 or tetrodotoxin-sensitive VGSC currents. MrVIB blocked human NaV1.8 expressed in Xenopus oocytes with selectivity at least 10-fold greater than other VGSCs. In neuropathic and chronic inflammatory pain models, allodynia and hyperalgesia were both reduced by intrathecal infusion of MrVIB (0.03-3 nmol), whereas motor side effects occurred only at 30-fold higher doses. In contrast, the nonselective VGSC blocker lignocaine displayed no selectivity for allodynia and hyperalgesia versus motor side effects. The actions of MrVIB reveal that VGSC antagonists displaying selectivity toward NaV1.8 can alleviate chronic pain behavior with a greater therapeutic index than nonselective antagonists.

AB - The tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na V1.8 is expressed predominantly by damage-sensing primary afferent nerves and is important for the development and maintenance of persistent pain states. Here we demonstrate that μO-conotoxin MrVIB from Conus marmoreus displays substantial selectivity for NaV1.9 and inhibits pain behavior in models of persistent pain. In rat sensory neurons, submicromolar concentrations of MrVIB blocked tetrodotoxin-resistant current characteristic of NaV1.8 but not NaV1.9 or tetrodotoxin-sensitive VGSC currents. MrVIB blocked human NaV1.8 expressed in Xenopus oocytes with selectivity at least 10-fold greater than other VGSCs. In neuropathic and chronic inflammatory pain models, allodynia and hyperalgesia were both reduced by intrathecal infusion of MrVIB (0.03-3 nmol), whereas motor side effects occurred only at 30-fold higher doses. In contrast, the nonselective VGSC blocker lignocaine displayed no selectivity for allodynia and hyperalgesia versus motor side effects. The actions of MrVIB reveal that VGSC antagonists displaying selectivity toward NaV1.8 can alleviate chronic pain behavior with a greater therapeutic index than nonselective antagonists.

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