PMID- 26646348
OWN - NLM
STAT- MEDLINE
DCOM- 20160706
LR  - 20210902
IS  - 1526-7598 (Electronic)
IS  - 0003-2999 (Linking)
VI  - 122
IP  - 3
DP  - 2016 Mar
TI  - R-Duloxetine and N-Methyl Duloxetine as Novel Analgesics Against Experimental 
      Postincisional Pain.
PG  - 719-729
LID - 10.1213/ANE.0000000000001086 [doi]
AB  - 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.
FAU - Wang, Chi-Fei
AU  - Wang CF
AD  - 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.
FAU - Russell, Gabriella
AU  - Russell G
FAU - Wang, Sho-Ya
AU  - Wang SY
FAU - Strichartz, Gary R
AU  - Strichartz GR
FAU - Wang, Ging Kuo
AU  - Wang GK
LA  - eng
GR  - CA080153/CA/NCI NIH HHS/United States
GR  - GM094152/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Anesth Analg
JT  - Anesthesia and analgesia
JID - 1310650
RN  - 0 (Analgesics)
RN  - 0 (Antidepressive Agents, Second-Generation)
RN  - 0 (N-methylduloxetine)
RN  - 0 (Sodium Channel Blockers)
RN  - 9044SC542W (Duloxetine Hydrochloride)
SB  - IM
MH  - Analgesics/*pharmacology
MH  - Animals
MH  - Antidepressive Agents, Second-Generation/*pharmacology
MH  - Cell Line
MH  - Duloxetine Hydrochloride/*analogs & derivatives/*pharmacology
MH  - Hyperalgesia/drug therapy
MH  - Injections, Intraperitoneal
MH  - Injections, Subcutaneous
MH  - Male
MH  - Neurons/drug effects
MH  - Pain, Postoperative/*drug therapy
MH  - Patch-Clamp Techniques
MH  - Physical Stimulation
MH  - Pituitary Gland/cytology/drug effects
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sodium Channel Blockers/pharmacology
EDAT- 2015/12/10 06:00
MHDA- 2016/07/07 06:00
CRDT- 2015/12/10 06:00
PHST- 2015/12/10 06:00 [entrez]
PHST- 2015/12/10 06:00 [pubmed]
PHST- 2016/07/07 06:00 [medline]
AID - 00000539-201603000-00020 [pii]
AID - 10.1213/ANE.0000000000001086 [doi]
PST - ppublish
SO  - Anesth Analg. 2016 Mar;122(3):719-729. doi: 10.1213/ANE.0000000000001086.