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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleNEUROPHARMACOLOGY

A Selective Nav1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], Attenuates Spinal Neuronal Activity in Neuropathic Rats

Steve McGaraughty, Katharine L. Chu, Marc J. C. Scanio, Michael E. Kort, Connie R. Faltynek and Michael F. Jarvis
Journal of Pharmacology and Experimental Therapeutics March 2008, 324 (3) 1204-1211; DOI: https://doi.org/10.1124/jpet.107.134148
Steve McGaraughty
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Katharine L. Chu
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Marc J. C. Scanio
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Michael E. Kort
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Connie R. Faltynek
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Michael F. Jarvis
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Abstract

We have recently reported that systemic delivery of A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], a selective Nav1.8 sodium channel blocker, reduces behavioral measures of chronic pain. In the current study, the effects of A-803467 on evoked and spontaneous firing of wide dynamic range (WDR) neurons were measured in uninjured and rats with spinal nerve ligations (SNLs). Administration of A-803467 (10–30 mg/kg i.v.) reduced mechanically evoked (10-g von Frey hair) and spontaneous WDR neuronal activity in SNL rats. In uninjured rats, A-803467 (20 mg/kg i.v.) transiently reduced evoked but not spontaneous firing of WDR neurons. The systemic effects of A-803467 in SNL rats were not altered by spinal transection or by systemic pretreatment with the transient receptor potential vanilloid type 1 (TRPV1) receptor agonist, resiniferatoxin, at doses that impair the function of TRPV1-expressing fibers. To determine sites of action, A-803467 was administered into spinal tissue, into the uninjured L4 dorsal root ganglion (DRG), or into the neuronal receptive field. Injections of A-803467 into the L4 DRG (30–100 nmol/1 μl) or into the hindpaw receptive field (300 nmol/50 μl) reduced evoked but not spontaneous WDR firing. In contrast, intraspinal (50–150 nmol/0.5 μl) injection of A-803467 decreased both evoked and spontaneous discharges of WDR neurons. Thus, Nav1.8 sodium channels on the cell bodies/axons within the L4 DRG as well as on peripheral and central terminals of primary afferent neurons regulate the inflow of low-intensity mechanical signals to spinal WDR neurons. However, Nav1.8 sodium channels on central terminals seem to be key to the modulation of spontaneous firing in SNL rats.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.134148.

  • ABBREVIATIONS: VGSC, voltage-gated sodium channel; WDR, wide dynamic range; SNL, sciatic nerve ligation; DRG, dorsal root ganglion; TRPV1, transient receptor potential vanilloid type 1; LTM, low-threshold mechanoreceptor.

    • Received November 9, 2007.
    • Accepted December 17, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 377 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 2
1 May 2021
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A Selective Nav1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], Attenuates Spinal Neuronal Activity in Neuropathic Rats
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Research ArticleNEUROPHARMACOLOGY

A Selective Nav1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], Attenuates Spinal Neuronal Activity in Neuropathic Rats

Steve McGaraughty, Katharine L. Chu, Marc J. C. Scanio, Michael E. Kort, Connie R. Faltynek and Michael F. Jarvis
Journal of Pharmacology and Experimental Therapeutics March 1, 2008, 324 (3) 1204-1211; DOI: https://doi.org/10.1124/jpet.107.134148

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Research ArticleNEUROPHARMACOLOGY

A Selective Nav1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], Attenuates Spinal Neuronal Activity in Neuropathic Rats

Steve McGaraughty, Katharine L. Chu, Marc J. C. Scanio, Michael E. Kort, Connie R. Faltynek and Michael F. Jarvis
Journal of Pharmacology and Experimental Therapeutics March 1, 2008, 324 (3) 1204-1211; DOI: https://doi.org/10.1124/jpet.107.134148
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