title: Spinal tonicaine: potency and differential blockade of sensory and motor functions.
abstract: BACKGROUND
  Long-acting local anesthetics are beneficial for the management of postoperative pain and chronic pain. The authors recently reported that a single injection of N-beta-phenylethyl-lidocaine (tonicaine), a quaternary lidocaine derivative, effectively blocks rat sciatic nerve function four to nine times longer than lidocaine, with a predominance of sensory versusmotor blockade. The purposes of this study were to measure directly the potency of this charged drug by internal perfusion of cultured neuronal cells, and to evaluate the differential blockade of sensory versus motor function via spinal route in rats.
  
  
  METHODS
  The tonic and additional use-dependent blockade of Na+ currents by internal tonicaine was assayed in cultured GH3 cells during whole cell voltage-clamp conditions. In addition, tonicaine was injected into the intrathecal space of rats at intervertebral space L4-L5, and the proprioceptive, motor, and sensory functions, and tissue integrity, subsequently were evaluated.
  
  
  RESULTS
  Internal application of tonicaine in GH3 cells revealed that it was approximately 80 times more potent in blocking Na+ currents than was externally applied lidocaine. In vivotesting in a rat neuraxial anesthesia model showed that tonicaine at 0.5 mm produced blockade that lasted much longer than that produced by bupivacaine even at approximately a 55 times higher concentration (28.8 mm). Tonicaine spinal block also produced a longer duration of sensory than motor blockade (112.5 +/- 16.3 min vs. 45.8 +/- 7.1 min). Evidence of neurotoxicity was seen at a concentration of 1.0 mm.
  
  
  CONCLUSIONS
  In vitro testing shows that tonicaine displays a higher affinity for the local anesthetic binding site than does lidocaine; in vivotesting indicates that tonicaine elicits sensory blockade of a duration significantly longer than that elicited by bupivacaine. Tonicaine, however, has a narrow therapeutic index, with substantial neurotoxicity at 1 mm in rats, and may have limited clinical value.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. gerner@zeus.bwh.harvard.edu
authors.forename: P
authors.initials: P
authors.lastname: Gerner
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: C F
authors.initials: CF
authors.lastname: Quan
authors.forename: D C
authors.initials: DC
authors.lastname: Anthony
authors.forename: G K
authors.initials: GK
authors.lastname: Wang
mesh_terms: D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D007278:Injections, Spinal; D008012:Lidocaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D009046:Motor Neurons / Q000187:drug effects*; D019148:Neuromuscular Blockade; D009475:Neurons, Afferent / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects; D013116:Spinal Cord / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000779:Anesthetics, Local; D015222:Sodium Channels; C097272:tonicaine; C012647:QX-314; D008012:Lidocaine