title: Nisoxetine blocks sodium currents and elicits spinal anesthesia in rats.
abstract: BACKGROUND
  Although nisoxetine has been shown to elicit infiltrative cutaneous local anesthesia, the inhibition of voltage-gated Na(+) channels by nisoxetine has not been reported. The aim of this study was to evaluate the effect of nisoxetine on Na(+) currents and its efficacy on spinal anesthesia.
  
  
  METHODS
  In in vitro studies, the voltage-clamp method was employed to examine whether nisoxetine blocked Na(+) currents in mouse neuroblastoma N2A cells.
  
  
  RESULTS
  Mepivacaine showed concentration- and state-dependent effect on tonic blockade of voltage-gated Na(+) currents (IC50 of 3.7 and 74.2 μM at holding potentials of -70 and -100 mV, respectively). Nisoxetine was more potent (IC50 of 1.6 and 28.6 μM at holding potentials of -70 and -100 mV, respectively). In in vivo studies, after rats were intrathecally injected with nisoxetine and mepivacaine, the dose-response curves were constructed. Nisoxetine acted like local anesthetic mepivacaine and induced spinal anesthesia with a more sensory-selective action (p < 0.05) over motor blockade in a dose-related fashion. Intrathecal 5% dextrose (vehicle) produced no spinal anesthesia. On the 50% effective dose (ED50) basis, nisoxetine elicited more potent spinal anesthesia than did mepivacaine (p < 0.05).
  
  
  CONCLUSIONS
  Our results showed that nisoxetine displayed a more potent and prolonged spinal anesthesia with a more sensory/nociceptive-selective action over motor blockade, compared with mepivacaine. The local anesthetic effect of nisoxetine could be probably due to the suppression of Na(+) currents.
authors.affiliation: Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung, Taiwan.
authors.forename: Yuk-Man
authors.initials: YM
authors.lastname: Leung
authors.forename: Chin-Chen
authors.initials: CC
authors.lastname: Chu
authors.forename: Chang-Shin
authors.initials: CS
authors.lastname: Kuo
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Jhi-Joung
authors.initials: JJ
authors.lastname: Wang
mesh_terms: D000775:Anesthesia, Spinal / Q000379:methods*; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007278:Injections, Spinal; D008297:Male; D008619:Mepivacaine / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D061567:Voltage-Gated Sodium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000187:drug effects / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D005473:Fluoxetine; C011386:nisoxetine; D008619:Mepivacaine