title: R-Duloxetine and N-Methyl Duloxetine as Novel Analgesics Against Experimental Postincisional Pain.
abstract: BACKGROUND
  Antidepressant S-duloxetine alleviates intractable pain associated with diabetic peripheral neuropathy and fibromyalgia. It also reduces both acute and persistent pain in various animal models. This study addresses whether the enantiomer, R-duloxetine, and the homolog, N-methyl duloxetine, could act as analgesics and whether they block neuronal Na⁺ channels.
  
  
  METHODS
  The rat incision plus extension model on the dorsothoracic skin was applied to evoke postoperative mechanoallodynia and hyperalgesia, measured for 5 days postoperatively by local responses to von Frey filaments. R-Duloxetine and N-methyl duloxetine were administered systemically (intraperitoneal) or locally (subcutaneous [SC]) 1 hour before the surgery. The block of Na currents in rat neuronal GH3 cells was determined under the whole-cell configuration.
  
  
  RESULTS
  Ipsilateral SC injections (2 mg/0.4 mL) of R-duloxetine and N-methyl duloxetine reduced both postoperative allodynia and hyperalgesia by approximately 89% to 99% in the area under the curve of skin responses next to incision over 5 days. Systemic intraperitoneal injections at a higher dosage (10 mg) had smaller analgesic effects (reduced by approximately 53%-69%), whereas contralateral SC injections (10 mg) were ineffective. Both R-duloxetine and N-methyl duloxetine blocked neuronal Na⁺ currents, with a higher affinity for the inactivated than the resting states. In addition, both drugs elicited significant use-dependent block of Na currents when stimulated at 5 Hz.
  
  
  CONCLUSIONS
  R-Duloxetine and N-methyl duloxetine are highly effective against postoperative pain using the skin incision model, and they elicit both tonic and use-dependent block of neuronal Na⁺ channels. Our results suggest that R-duloxetine and N-methyl duloxetine are applicable as novel analgesics.
authors.affiliation: From the College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women's Hospital, Boston, Massachusetts; and Department of Biological Sciences, SUNY at Albany, Albany, New York.
authors.forename: Chi-Fei
authors.initials: CF
authors.lastname: Wang
authors.forename: Gabriella
authors.initials: G
authors.lastname: Russell
authors.forename: Sho-Ya
authors.initials: SY
authors.lastname: Wang
authors.forename: Gary R
authors.initials: GR
authors.lastname: Strichartz
authors.forename: Ging Kuo
authors.initials: GK
authors.lastname: Wang
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D002460:Cell Line; D000068736:Duloxetine Hydrochloride / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D009474:Neurons / Q000187:drug effects; D010149:Postoperative Pain / Q000188:drug therapy*; D018408:Patch-Clamp Techniques; D010812:Physical Stimulation; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D000700:Analgesics; D018687:Antidepressive Agents, Second-Generation; C000608813:N-methylduloxetine; D026941:Sodium Channel Blockers; D000068736:Duloxetine Hydrochloride