Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats.
5-Hydroxytryptamine (serotonin) (5-HT) and norepinephrine (NE) are implicated in modulating descending inhibitory pain pathways in the central nervous system. Duloxetine is a selective and potent dual 5-HT and NE reuptake inhibitor (SNRI). The ability of duloxetine to antagonize 5-HT depletion in para-chloramphetamine-treated rats was comparable with that of paroxetine, a selective serotonin reuptake inhibitor (SSRI), whereas its ability to antagonize NE depletion in alpha-methyl-m-tyrosine-treated rats was similar to norepinephrine reuptake inhibitors (NRIs), thionisoxetine or desipramine. In this paradigm, duloxetine was also more potent than other SNRIs, including venlafaxine or milnacipran and amitriptyline. Low doses of the SSRI paroxetine or the NRI thionisoxetine alone did not have an effect on late phase paw-licking pain behavior in the formalin model of persistent pain; however, when combined, significantly attenuated this pain behavior. Duloxetine (3-15 mg/kg intraperitoneal) significantly attenuated late phase paw-licking behavior in a dose-dependent manner in the formalin model and was more potent than venlafaxine, milnacipran, and amitriptyline. These effects of duloxetine were evident at doses that did not cause neurologic deficits in the rotorod test. Duloxetine (5-30 mg/kg oral) was also more potent and efficacious than venlafaxine and milnacipran in reversing mechanical allodynia behavior in the L5/L6 spinal nerve ligation model of neuropathic pain. Duloxetine (3-30 mg/kg oral) was minimally efficacious in the tail-flick model of acute nociceptive pain. These data suggest that inhibition of both 5-HT and NE uptake may account for attenuation of persistent pain mechanisms. Thus, duloxetine may have utility in treatment of human persistent and neuropathic pain states.
Iyengar
Smriti
S
Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA. iyengar@lilly.com
Webster
Amy A
AA
Hemrick-Luecke
Susan K
SK
Xu
Jimmy Yu
JY
Simmons
Rosa Maria A
RM
D000208:Acute Disease; D000588:Amines / Q000627:therapeutic use; D000639:Amitriptyline / Q000627:therapeutic use; D000818:Animals; D016292:Procedural Sedation; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use; D003511:Cyclohexanols / Q000627:therapeutic use; D003521:Cyclopropanes / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D000068736:Duloxetine Hydrochloride; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005557:Formaldehyde; D000077206:Gabapentin; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D000078764:Milnacipran; D009469:Neuromuscular Junction / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D017374:Paroxetine / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D013876:Thiophenes / Q000627:therapeutic use*; D000069470:Venlafaxine Hydrochloride; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use; D010133:p-Chloroamphetamine / Q000494:pharmacology
D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D003511:Cyclohexanols; D003521:Cyclopropanes; D008781:Methyltyrosines; D013876:Thiophenes; D005473:Fluoxetine; D000639:Amitriptyline; D005557:Formaldehyde; C093518:thionisoxetine; D012701:Serotonin; D017374:Paroxetine; D005680:gamma-Aminobutyric Acid; D010133:p-Chloroamphetamine; D000077206:Gabapentin; D000069470:Venlafaxine Hydrochloride; D000068736:Duloxetine Hydrochloride; C031476:alpha-methyl-m-tyrosine; D000078764:Milnacipran; D009638:Norepinephrine