title: The scorpion toxin Amm VIII induces pain hypersensitivity through gain-of-function of TTX-sensitive Na⁺ channels.
abstract: 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.
authors.affiliation: Aix-Marseille-Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, UMR 7286 Marseille, France.
authors.forename: Najwa
authors.initials: N
authors.lastname: Abbas
authors.forename: Christelle
authors.initials: C
authors.lastname: Gaudioso-Tyzra
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonnet
authors.forename: Mélanie
authors.initials: M
authors.lastname: Gabriac
authors.forename: Muriel
authors.initials: M
authors.lastname: Amsalem
authors.forename: Aurélie
authors.initials: A
authors.lastname: Lonigro
authors.forename: Françoise
authors.initials: F
authors.lastname: Padilla
authors.forename: Marcel
authors.initials: M
authors.lastname: Crest
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Martin-Eauclaire
authors.forename: Patrick
authors.initials: P
authors.lastname: Delmas
mesh_terms: D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D006967:Hypersensitivity / Q000188:drug therapy / Q000209:etiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects; D010146:Pain / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D012604:Scorpion Venoms / Q000494:pharmacology / Q000633:toxicity*; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C484037:Amm VIII toxin, Androctonus mauretanicus mauretanicus; D012604:Scorpion Venoms; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin