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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 1, 2006; DOI: 10.1124/jpet.106.109728

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Received for publication June 22, 2006.
Revised November 30, 2006.
Accepted for publication November 30, 2006.

Differential and Synergistic Effects of Selective Norepinephrine and Serotonin Reuptake Inhibitors in Rodent Models of Pain

Liza Leventhal 1*, Valerie A. Smith 1, Geoffrey Hornby 2, Terrance H. Andree 1, Michael R. Brandt 1, Kathryn E. Rogers 1

1 Wyeth Research 2 Wyeth Researach

* Address correspondence to: E-mail: leventl{at}wyeth.com

Abstract

There is increasing recognition that norepinephrine (NE) and serotonin (5-HT) reuptake inhibitors (NRIs and SRIs) are efficacious in treating some types of pain. To date studies have not systematically evaluated the relative activity at the NE and/or 5-HT transporter required for maximal efficacy in rodent pain models. Known selective NE and 5-HT reuptake inhibitors: reboxetine, desipramine, fluoxetine and paroxetine were evaluated in both in vitro and in vivo assays. Utilizing the spinal nerve ligation model of neuropathic pain, the compounds differentially reversed tactile allodynia. Evaluation of a broader spectrum of reuptake inhibitors in the para-phenylquinone (PPQ)-induced abdominal constriction model, a model of acute visceral pain, demonstrated that both the SRIs and the NRIs significantly blocked abdominal constrictions. However, the magnitude of this effect was greater following treatment with compounds having greater affinity for NRI as compared to SRI affinity. Additionally, isobolographic analyses indicated significant synergistic effects for all combinations of desipramine and fluoxetine in the PPQ model of visceral pain. Collectively, the present results support the hypothesis that compounds with greater NRI activity should be more effective for the treatment of pain than compounds having only SRI activity and this hypothesis is also supported by clinical data. These studies also suggest that the potency and effectiveness of NRIs might be enhanced by the presence of 5-HT activity.


Key words: antidepressant, isobologram, neuropathic pain, norepinephrine, serotonin, visceral pain


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