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, L., Mould, J., Drinkwater, R., Baker, M.D., Abrahamsen, B., Wood, J.N., Adams, D.J., Christie, M.J., and Lewis, R.J. (2006) μO-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits. National Academy of Sciences. Proceedings, 103 (45). p. 17035.
|PDF - Repository staff only - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader|
View at Publisher Website: http://dx.doi.org/10.1073/pnas.060181910...
The tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Nav1.8 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 Nav1.8 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.
|Item Type:||Article (Refereed Research - C1)|
|Keywords:||electrophysiology; pain model; dorsal root ganglia; allodynia|
|FoR Codes:||11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics @ 40%|
|Deposited On:||10 Jul 2009 13:35|
|Last Modified:||13 Feb 2011 18:23|
Last 12 Months: 0
Repository Staff Only: item control page