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Cellular Mechanisms Mediating the Antinociceptive Effect of Botulinum Toxin A in a Rodent Model of Trigeminal Irritation by a Foreign Body

  • Author Footnotes
    a These authors contributed equally to this study.
    Jin H. Cho
    Footnotes
    a These authors contributed equally to this study.
    Affiliations
    Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, Korea
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  • Author Footnotes
    a These authors contributed equally to this study.
    Jo Y. Son
    Footnotes
    a These authors contributed equally to this study.
    Affiliations
    Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, Korea
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  • Jin S. Ju
    Affiliations
    Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, Korea
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  • Yu M. Kim
    Affiliations
    Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, Korea
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  • Dong K. Ahn
    Correspondence
    Address reprint requests to Dong-Kuk, Ahn, DDS, PhD, Department of Oral Physiology, School of Dentistry, Kyungpook National University, 2177, Dalgubeol-daero, Jung-gu, Daegu, 41940, Korea.
    Affiliations
    Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, Korea
    Search for articles by this author
  • Author Footnotes
    a These authors contributed equally to this study.
Published:September 07, 2022DOI:https://doi.org/10.1016/j.jpain.2022.08.004

      Highlights

      • Compression of TNR increases HIF-1α expression and IL-1β, IL-6, and TNF-α concentrations in TG.
      • BTX-A produces prolonged antinociception and suppresses HIF-1α and cytokine concentrations.
      • Intraganglionic PX-12 injection produces anti-allodynic effects and lower cytokines levels in TG.

      Abstract

      Although numerous studies have described botulinum toxin type A (BTX-A) efficacy against trigeminal neuralgia (TN), the underlying cellular mechanisms remain unclear. We have investigated cellular mechanisms that mediate the antinociceptive effect of BTX-A in a rodent model of TN produced by compression of the trigeminal nerve root (TNR). Anesthetized male Sprague-Dawley rats were fixed in a stereotaxic instrument and compression of the TNR was then achieved with a 4% agar solution. This model produced a significant mechanical allodynia and increased the expression of hypoxia-inducible factor (HIF)-1α and cytokines levels including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the trigeminal ganglion (TG) by postoperative day (POD) 7. Single or double treatments with a high BTX-A dose (3 U/kg) led to significantly prolonged antinociceptive effects. Furthermore, a single treatment with BTX-A (3 U/kg) significantly suppressed the upregulation of HIF-1α expression and IL-1β, IL-6, and TNF-α concentrations in the TG. Intraganglionic injection of PX-12, a HIF-1α inhibitor, led to significant anti-allodynic effects and lowered the IL-1β, IL-6, and TNF-α levels in the TG. These findings indicate that the antinociceptive effect of BTX-A is mediated via HIF-1α associated cytokines modulation in the TG and is therefore a potentially relevant treatment strategy for TN.

      Perspective

      The antinociceptive properties of BTX-A in a rat model of trigeminal neuralgia are mediated through the regulation of the HIF-1α associated cytokine pathway in the trigeminal ganglion. BTX-A is therefore a potentially effective treatment strategy for trigeminal neuralgia.

      Key words

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