Received for publication April 29, 2004.
Revised June 30, 2004.
Accepted for publication July 1, 2004.

Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats

Abstract

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 parachloramphetamine (p-CA)-treated rats was comparable to paroxetine, a selective serotonin reuptake inhibitor (SSRI), while its ability to antagonize NE depletion in -methyl-m-tyrosine (-MMT)-treated rats was similar to norepinephrine reuptake inhibitors (NRI), 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.

Key words: duloxetine, neuropathic, norepinephrine, pain, reuptake inhibitor, serotonin

This article has been cited by other articles:

				P. A. Krieter, M. Gohdes, T. J. Musick, F. P. Duncanson, and W. E. Bridson Pharmacokinetics, Disposition, and Metabolism of Bicifadine in Humans Drug Metab. Dispos., February 1, 2008; 36(2): 252 - 259. [Abstract] [Full Text] [PDF]

				A. S. Basile, A. Janowsky, K. Golembiowska, M. Kowalska, E. Tam, M. Benveniste, P. Popik, A. Nikiforuk, M. Krawczyk, G. Nowak, et al. Characterization of the Antinociceptive Actions of Bicifadine in Models of Acute, Persistent, and Chronic Pain J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 1208 - 1225. [Abstract] [Full Text] [PDF]

				Z.-Q. Zhao, S. Chiechio, Y.-G. Sun, K.-H. Zhang, C.-S. Zhao, M. Scott, R. L. Johnson, E. S. Deneris, K. J. Renner, R. W. Gereau IV, et al. Mice Lacking Central Serotonergic Neurons Show Enhanced Inflammatory Pain and an Impaired Analgesic Response to Antidepressant Drugs J. Neurosci., May 30, 2007; 27(22): 6045 - 6053. [Abstract] [Full Text] [PDF]

				L. Leventhal, V. Smith, G. Hornby, T. H. Andree, M. R. Brandt, and K. E. Rogers Differential and Synergistic Effects of Selective Norepinephrine and Serotonin Reuptake Inhibitors in Rodent Models of Pain J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 1178 - 1185. [Abstract] [Full Text] [PDF]

				D. C. Deecher, C. E. Beyer, G. Johnston, J. Bray, S. Shah, M. Abou-Gharbia, and T. H. Andree Desvenlafaxine Succinate: A New Serotonin and Norepinephrine Reuptake Inhibitor J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 657 - 665. [Abstract] [Full Text] [PDF]

				C. K. Jones, S. C. Peters, and H. E. Shannon Efficacy of Duloxetine, a Potent and Balanced Serotonergic and Noradrenergic Reuptake Inhibitor, in Inflammatory and Acute Pain Models in Rodents J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 726 - 732. [Abstract] [Full Text] [PDF]