Sea-Anemone Toxin ATX-II Elicits A-Fiber-Dependent Pain and Enhances Resurgent and Persistent Sodium Currents in Large Sensory Neurons

Background: Gain-of-function mutations of the nociceptive voltage-gated sodium channel Nav1.7 lead to inherited pain syndromes, such as paroxysmal extreme pain disorder (PEPD). One characteristic of these mutations is slowed fast-inactivation kinetics, which may give rise to resurgent sodium current...

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Published in:	Molecular pain 2012-09, Vol.8 (1), p.69-69
Main Authors:	Klinger, Alexandra B, Eberhardt, Mirjam, Link, Andrea S, Namer, Barbara, Kutsche, Lisa K, Schuy, E Theresa, Sittl, Ruth, Hoffmann, Tali, Alzheimer, Christian, Huth, Tobias, Carr, Richard W, Lampert, Angelika
Format:	Article
Language:	eng
Subjects:	Anemonia sulcata Anesthesiology Animals Cnidarian Venoms - administration & dosage Cnidarian Venoms - toxicity Design Differential nerve block Experiments Extracellular Space - drug effects Extracellular Space - metabolism Female Ganglia, Spinal - drug effects Ganglia, Spinal - pathology Ganglia, Spinal - physiopathology Genetic aspects HEK293 Cells Humans Injections, Intradermal Ion Channel Gating - drug effects Itch Male Mice Mutation NAV1.6 Voltage-Gated Sodium Channel - metabolism NAV1.7 Voltage-Gated Sodium Channel - metabolism Nerve Fibers, Myelinated - drug effects Nerve Fibers, Myelinated - metabolism Nerve Fibers, Myelinated - pathology Neurons Pain Pain - pathology Pain - physiopathology Patch-clamp Peptides Peptides - toxicity Pruritus - pathology Pruritus - physiopathology Psychophysics RT-qPCR SCN4b Sensory neurons Sensory Receptor Cells - drug effects Sensory Receptor Cells - metabolism Sensory Receptor Cells - pathology Skin Sodium Sodium channels Sodium Channels - metabolism Temperature effects Time Factors
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Summary:	Background: Gain-of-function mutations of the nociceptive voltage-gated sodium channel Nav1.7 lead to inherited pain syndromes, such as paroxysmal extreme pain disorder (PEPD). One characteristic of these mutations is slowed fast-inactivation kinetics, which may give rise to resurgent sodium currents. It is long known that toxins from Anemonia sulcata, such as ATX-II, slow fast inactivation and skin contact for example during diving leads to various symptoms such as pain and itch. Here, we investigated if ATX-II induces resurgent currents in sensory neurons of the dorsal root ganglion (DRGs) and how this may translate into human sensations. Results: In large A-fiber related DRGs ATX-II (5 nM) enhances persistent and resurgent sodium currents, but failed to do so in small C-fiber linked DRGs when investigated using the whole-cell patch-clamp technique. Resurgent currents are thought to depend on the presence of the sodium channel β4-subunit. Using RT-qPCR experiments, we show that small DRGs express significantly less β4 mRNA than large sensory neurons. With the β4-C-terminus peptide in the pipette solution, it was possible to evoke resurgent currents in small DRGs and in Nav1.7 or Nav1.6 expressing HEK293/N1E115 cells, which were enhanced by the presence of extracellular ATX-II. When injected into the skin of healthy volunteers, ATX-II induces painful and itch-like sensations which were abolished by mechanical nerve block. Increase in superficial blood flow of the skin, measured by Laser doppler imaging is limited to the injection site, so no axon reflex erythema as a correlate for C-fiber activation was detected. Conclusion: ATX-II enhances persistent and resurgent sodium currents in large diameter DRGs, whereas small DRGs depend on the addition of β4-peptide to the pipette recording solution for ATX-II to affect resurgent currents. Mechanical A-fiber blockade abolishes all ATX-II effects in human skin (e.g. painful and itch-like paraesthesias), suggesting that it mediates its effects mainly via activation of A-fibers.
ISSN:	1744-8069 1744-8069