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Research ArticleArticle

Antinociceptive Properties of Fenfluramine, a Serotonin Reuptake Inhibitor, in a Rat Model of Neuropathy

Yong-Xiang Wang, S. Scott Bowersox, Mark Pettus and Da Gao
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1008-1016;
Yong-Xiang Wang
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S. Scott Bowersox
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Mark Pettus
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Da Gao
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Abstract

Fenfluramine is an indirect agonist of 5-hydroxytryptamine (5-HT) receptors that acts by evoking 5-HT release and blocking 5-HT reuptake in neuronal cells. The current study compared the antinociceptive properties of fenfluramine with those of the tricyclic antidepressants amitriptyline and desipramine in rat models of acute, persistent, and neuropathic pain. In a rat model of neuropathic pain produced by tight ligation of the L5/L6 spinal nerves, i.v. bolus injection of fenfluramine resulted in a dose-dependent and long-lasting (>4 h) blockade of mechanical allodynia (ED50 = 3.5 mg/kg; 95% confidence interval, 2.2–5.4 mg/kg) and cold allodynia (ED50 = 2.4 mg/kg; 95% confidence range, 1.2–4.6 mg/kg). Fenfluramine also prevented tonic pain evoked by the s.c. injection of dilute (5%) formaldehyde solution (formalin), into the dorsal hindpaw. The i.v. administration of amitriptyline (4.7 mg/kg) or desipramine (13.5 mg/kg) at maximum tolerated doses did not block either allodynia in rats with spinal nerve ligation-induced painful neuropathy or tonic pain in the formalin test. Fenfluramine had differential effects on acute behavioral responses to noxious thermal (heat), chemical (5% formaldehyde solution), and mechanical stimuli; it completely inhibited nociceptive behavior in the acute phase of the formaldehyde solution test and partially inhibited licking and jumping responses in the hot-plate test but did not alter nociceptive thresholds in either the paw pressure test or the tail immersion test. Intracerebroventricular bolus injection of 240 μg of fenfluramine significantly increased mechanical allodynia thresholds; however, the same dose administered spinally by intrathecal bolus injection was ineffective. The inhibitory effects of fenfluramine on mechanical allodynia (and tonic pain behavior in the formaldehyde solution test) were prevented by pretreatment with 10 mg/kg metergoline, a selective antagonist of 5-HT receptors, but not with the μ-opioid receptor antagonist naloxone. These results suggest that fenfluramine produces analgesia in the formaldehyde solution test and the spinal nerve ligation model of neuropathic pain by potentiating, at least in part, supraspinal 5-HT mediated processes.

Footnotes

  • Send reprint requests to: Yong-Xiang Wang, M.D., Ph.D., Department of Pharmacology, Elan Pharmaceuticals, 3760 Haven Ave., Menlo Park, CA 94025. E-mail: jwang{at}elanpharma.com

  • Abbreviations:
    5-HT
    5-hydroxytryptamine
    SNL
    spinal nerve ligation
    MPE
    maximum possible effect
    i.t.
    intrathecal
    AUC
    area under the time-effect curve
    • Received April 14, 1999.
    • Accepted July 18, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Antinociceptive Properties of Fenfluramine, a Serotonin Reuptake Inhibitor, in a Rat Model of Neuropathy

Yong-Xiang Wang, S. Scott Bowersox, Mark Pettus and Da Gao
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1008-1016;

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Research ArticleArticle

Antinociceptive Properties of Fenfluramine, a Serotonin Reuptake Inhibitor, in a Rat Model of Neuropathy

Yong-Xiang Wang, S. Scott Bowersox, Mark Pettus and Da Gao
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1008-1016;
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