Combination Drug Therapy of Pioglitazone and D-cycloserine Attenuates Chronic Orofacial Neuropathic Pain and Anxiety by Improving Mitochondrial Function Following Trigeminal Nerve Injury

Danielle N. Lyons, Liping Zhang, Jignesh D. Pandya, Robert J. Danaher, Fei Ma, Craig S. Miller, Patrick G. Sullivan, Cristian Sirbu, Karin N. Westlund

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Objectives: The study aim was to determine how peripheral trigeminal nerve injury affects mitochondrial respiration and to test efficacy of combined treatment with 2 Federal Drug Administration approved drugs with potential for improving mitochondrial bioenergetics, pain and anxiety-related behaviors in a chronic orofacial neuropathic pain mouse model. Methods: Efficacy of (R)-(+)-4-amino-3-isoxazolidinone (D-cycloserine, DCS), an N-Methyl-D-aspartate antagonist/agonist, and Pioglitazone (PIO), a selective agonist of nuclear receptor peroxisome proliferator-activated receptor gamma was investigate in the trigeminal inflammatory compression (TIC) neuropathic nerve injury mouse model. Combined low doses of these drugs (80mg/kg DCS and 100mg/kg PIO) were given as a single bolus or daily for 7 days post- TIC to test ability to attenuate neuropathic nociceptive and associated cognitive dependent anxiety behaviors. In addition, beneficial effects of the DCS/PIO drug combination were explored ex vivo in isolated cortex/brainstem mitochondria at 28 weeks post-TIC. Results: The DCS/PIO combination not only attenuated orofacial neuropathic pain and anxiety-related behaviors associated with trigeminal nerve injury, but it also improved mitochondrial bioenergetics. Discussion: The DCS/PIO combination uncoupled mitochondrial respiration in the TIC model to improve cortical mitochondrial dysfunction, as well as reduced nociceptive and anxiety behaviors present in mice with centralized chronic neuropathic nerve injury. Combining these drugs could be a beneficial treatment for patients with depression, anxiety, or other psychological conditions due to their chronic pain status.

Original languageEnglish
Pages (from-to)168-177
Number of pages10
JournalClinical Journal of Pain
Volume34
Issue number2
DOIs
StatePublished - 2018

Bibliographical note

Publisher Copyright:
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Keywords

  • 2,4-DNP
  • bioscience seahorse XFe24 flux analyzer
  • clinical translational
  • light-dark box place preference test
  • mechanical allodynia
  • mice
  • mitochondrial bioenergetics
  • mitochondrial electron transport chain
  • respiratory control ratio
  • trigeminal inflammatory compression (TIC) injury

ASJC Scopus subject areas

  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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