title: The Local and Systemic Actions of Duloxetine in Allodynia and Hyperalgesia Using a Rat Skin Incision Pain Model.
abstract: BACKGROUND
  Duloxetine is an antidepressant effective for major depressive disorder and also the alleviation of pain for patients with diabetic peripheral neuropathy, chronic musculoskeletal pain, and fibromyalgia. How duloxetine works in pain relief remains unknown. In this study, we address whether duloxetine could act as an analgesic via systemic and local applications.
  
  
  METHODS
  Efficacies of bupivacaine and duloxetine applied subcutaneously at the incision site against acute postoperative pain were compared after rat skin incision. Contralateral and intraperitoneal injections were used to assess systemic efficacy of duloxetine. Local anesthetic actions were assayed through functional block of the rat sciatic nerve. Inhibition by duloxetine of neuronal Na channels was characterized in rat GH3 cells.
  
  
  RESULTS
  Our studies showed that subcutaneous duloxetine (2 mg) reduced hyperalgesia and allodynia for several days after skin incision, whereas subcutaneous bupivacaine (2 mg) did not. Contralaterally injected duloxetine (10 mg) had minimal effects on postoperative pain. Intraperitoneal duloxetine also reduced both allodynia and hyperalgesia, albeit at higher doses (10-20 mg). Duloxetine (2 mg) inhibited motor and nociceptive functions via sciatic nerve block for approximately 24 hours. It also reduced Na currents with 50% inhibitory concentrations of 30.4 ± 1.2 μM and 4.26 ± 0.19 μM (n = 8) for resting and fast-inactivated channels, respectively. Furthermore, duloxetine (10 μM) elicited additional use-dependent block of peak Na currents by approximately 70% when stimulated at 5 Hz.
  
  
  CONCLUSIONS
  Our results demonstrate that duloxetine can act as a local anesthetic and an analgesic drug via both local and systemic applications. Because duloxetine inhibits neuronal Na currents with high potency, it may exert its antihyperalgesic effects through inhibition of the spontaneous nerve impulses that result from peripheral injury, encompassing its actions on multiple central nervous system and peripheral targets.
authors.affiliation: From the Department of Anesthesiology, Perioperative, Pain Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Chi-Fei
authors.initials: CF
authors.lastname: Wang
authors.forename: Gabriella
authors.initials: G
authors.lastname: Russell
authors.forename: Gary R
authors.initials: GR
authors.lastname: Strichartz
authors.forename: Ging-Kuo
authors.initials: GK
authors.lastname: Wang
mesh_terms: D000279:Administration, Cutaneous; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology; D002478:Cells, Cultured; D062109:Dermatologic Surgical Procedures; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride; D006930:Hyperalgesia / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D008297:Male; D010147:Pain Measurement; D010149:Postoperative Pain / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000700:Analgesics; D000779:Anesthetics, Local; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013876:Thiophenes; D000068736:Duloxetine Hydrochloride; D002045:Bupivacaine