title: Neurosteroids allopregnanolone sulfate and pregnanolone sulfate have diverse effect on the α subunit of the neuronal voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 expressed in xenopus oocytes.
abstract: BACKGROUND
  The neurosteroids allopregnanolone and pregnanolone are potent positive modulators of γ-aminobutyric acid type A receptors. Antinociceptive effects of allopregnanolone have attracted much attention because recent reports have indicated the potential of allopregnanolone as a therapeutic agent for refractory pain. However, the analgesic mechanisms of allopregnanolone are still unclear. Voltage-gated sodium channels (Nav) are thought to play important roles in inflammatory and neuropathic pain, but there have been few investigations on the effects of allopregnanolone on sodium channels.
  
  
  METHODS
  Using voltage-clamp techniques, the effects of allopregnanolone sulfate (APAS) and pregnanolone sulfate (PAS) on sodium current were examined in Xenopus oocytes expressing Nav1.2, Nav1.6, Nav1.7, and Nav1.8 α subunits.
  
  
  RESULTS
  APAS suppressed sodium currents of Nav1.2, Nav1.6, and Nav1.7 at a holding potential causing half-maximal current in a concentration-dependent manner, whereas it markedly enhanced sodium current of Nav1.8 at a holding potential causing maximal current. Half-maximal inhibitory concentration values for Nav1.2, Nav1.6, and Nav1.7 were 12 ± 4 (n = 6), 41 ± 2 (n = 7), and 131 ± 15 (n = 5) μmol/l (mean ± SEM), respectively. The effects of PAS were lower than those of APAS. From gating analysis, two compounds increased inactivation of all α subunits, while they showed different actions on activation of each α subunit. Moreover, two compounds showed a use-dependent block on Nav1.2, Nav1.6, and Nav1.7.
  
  
  CONCLUSIONS
  APAS and PAS have diverse effects on sodium currents in oocytes expressing four α subunits. APAS inhibited the sodium currents of Nav1.2 most strongly.
authors.affiliation: From the Department of Anesthesiology (T.H., D.O., T.M., T.K., T.S.) and Department of Pharmacology (N.Y.), School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan; Department of Occupational Toxicology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan (S.U.); Department of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan (Y.S.); and Cancer Pathophysiology Division, National Cancer Center Research Institute, Tokyo, Japan (Y.U.).
authors.forename: Takafumi
authors.initials: T
authors.lastname: Horishita
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
authors.forename: Susumu
authors.initials: S
authors.lastname: Ueno
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sudo
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Uezono
authors.forename: Dan
authors.initials: D
authors.lastname: Okura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Minami
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Takeyoshi
authors.initials: T
authors.lastname: Sata
mesh_terms: D000818:Animals; D005260:Female; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000187:drug effects; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000187:drug effects; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000187:drug effects; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000187:drug effects; D011280:Pregnanolone / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects; D061566:Voltage-Gated Sodium Channels / Q000187:drug effects* / Q000502:physiology; D014982:Xenopus laevis
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D011963:Receptors, GABA-A; D061566:Voltage-Gated Sodium Channels; D011280:Pregnanolone