title: Assessment of differential blockade by amitriptyline and its N-methyl derivative in different species by different routes.
abstract: BACKGROUND
  Increasing the duration of local anesthesia and/or creating greater differential blockade (i.e., selective block of pain-transmitting nerve fibers) has been attempted by modifying currently available agents. Most drugs show a different profile depending on the model or species studied. This study was designed to investigate the differential nerve-blocking properties of amitriptyline and its quaternary ammonium derivative in rats and sheep.
  
  
  METHODS
  The Na+ channel-blocking properties of N-methyl amitriptyline were determined with the patch clamp technique in cultured GH(3) cells. Various functions (motor, nociception, proprioception-ataxia) were compared in rats (spinal and sciatic nerve blockade) and sheep (spinal blockade) with amitriptyline, N-methyl amitriptyline, lidocaine, and bupivacaine (partially from historical data).
  
  
  RESULTS
  In vitro testing revealed N-methyl amitriptyline to be a potent Na+ channel blocker similar to amitriptyline but with a much longer duration of action. All drug concentrations tested in both the sciatic nerve model and the spinal block model produced no significant differential blockade in rats. Three of six rats in the 20-mM N-methyl amitriptyline group showed residual blockade 4 days after sciatic nerve injection. However, in the sheep spinal model, amitriptyline and in particular N-methyl amitriptyline displayed significant differential blockade at most time points. Sheep data for lidocaine and bupivacaine seemed to be more comparable to the clinical experience in humans than did rat data.
  
  
  CONCLUSIONS
  Amitriptyline and N-methyl amitriptyline are potent Na+ channel blockers and show greater differential blockade in sheep than in rats. This differential blockade in sheep is greater than that produced by lidocaine or bupivacaine.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. pgerner@partners.org
authors.forename: Peter
authors.initials: P
authors.lastname: Gerner
authors.forename: Anna E
authors.initials: AE
authors.lastname: Haderer
authors.forename: Mustafa
authors.initials: M
authors.lastname: Mujtaba
authors.forename: Yukari
authors.initials: Y
authors.lastname: Sudoh
authors.forename: Sanjeet
authors.initials: S
authors.lastname: Narang
authors.forename: Salahadin
authors.initials: S
authors.lastname: Abdi
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Srinivasa
authors.forename: Christof
authors.initials: C
authors.lastname: Pertl
authors.forename: Ging Kuo
authors.initials: GK
authors.lastname: Wang
mesh_terms: D000639:Amitriptyline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000775:Anesthesia, Spinal; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D004594:Electrophysiology; D005260:Female; D008012:Lidocaine / Q000494:pharmacology; D009407:Nerve Block; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology; D012756:Sheep; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects; D013045:Species Specificity
chemical_list: D000779:Anesthetics, Local; D000929:Antidepressive Agents, Tricyclic; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000639:Amitriptyline; C007479:dimethylprotriptyline; D008012:Lidocaine