ArticleThe scorpion toxin Amm VIII induces pain hypersensitivity through gain-of-function of TTX-sensitive Na+ channelsAbbas, Najwa1; Gaudioso-Tyzra, Christelle1; Bonnet, Caroline; Gabriac, Mélanie; Amsalem, Muriel; Lonigro, Aurélie; Padilla, Françoise; Crest, Marcel; Martin-Eauclaire, Marie-France; Delmas, Patrick*Author Information Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Aix-Marseille-Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, UMR 7286 Marseille, France *Corresponding author. Address: Aix-Marseille-Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, UMR 7286, CS80011, Bd Pierre Dramard, Marseille Cedex 15 13344, France. Tel.: +33 4 91 69 89 78; fax: +33 4 91 69 89 77. 1These authors have contributed equally to this work. E-mail address: [email protected] Submitted 19 September 2012; revised 27 February 2013; accepted 25 March 2013. Pain: August 2013 - Volume 154 - Issue 8 - p 1204-1215 doi: 10.1016/j.pain.2013.03.037 Buy Metrics Abstract The scorpion α-toxin Amm VIII causes mechanical and thermal pain hypersensitivities through gain-of-function of TTX-sensitive Na+ channels in pain transmitting neurons. Voltage-gated Na+ channels (Nav) are the targets of a variety of scorpion toxins. Here, we investigated the effects of Amm VIII, a toxin isolated from the venom of the scorpion Androctonus mauretanicus mauretanicus, on pain-related behaviours in mice. The effects of Amm VIII were compared with the classic scorpion α-toxin AaH II from Androctonus australis. Contrary to AaH II, intraplantar injection of Amm VIII at relatively high concentrations caused little nocifensive behaviours. However, Amm VIII induced rapid mechanical and thermal pain hypersensitivities. We evaluated the toxins’ effects on Nav currents in nociceptive dorsal root ganglion (DRG) neurons and immortalized DRG neuron-derived F11 cells. Amm VIII and AaH II enhanced tetrodotoxin-sensitive (TTX-S) Nav currents in DRG and F11 cells. Both toxins impaired fast inactivation and negatively shifted activation. AaH II was more potent than Amm VIII at modulating TTX-S Nav currents with EC50 of 5 nM and 1 μM, respectively. AaH II and Amm VIII also impaired fast inactivation of Nav1.7, with EC50 of 6.8 nM and 1.76 μM, respectively. Neither Nav1.8 nor Nav1.9 was affected by the toxins. AaH II and Amm VIII reduced first spike latency and lowered action potential threshold. Amm VIII was less efficient than AaH II in increasing the gain of the firing frequency-stimulation relationship. In conclusion, our data show that Amm VIII, although less potent than AaH II, acts as a gating-modifier peptide reminiscent of classic α-toxins, and suggest that its hyperalgesic effects can be ascribed to gain-of-function of TTX-S Na+ channels in nociceptors. © 2013 Lippincott Williams & Wilkins, Inc.