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

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

doi: 10.1097/AJP.0000000000000515
Original Articles

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 (80 mg/kg DCS and 100 mg/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.

Departments of *Physiology

Oral Health Practice

Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY

§Charleston Area Medical Center Health Education and Research Institute, Department of Behavioral Medicine and Psychiatry West Virginia University School of Medicine Charleston Division, Morgantown, WV

Present Address: Jignesh D. Pandya, PhD, Brain Trauma Neuroprotection and Neurorestoration (BTNN) Branch, Center for Military Psychiatry and Neuroscience (CMPN), Walter Reed Army Institute of Research (WRAIR), 503 Robert Grant Avenue, Silver Spring, MD 20910.

K.N.W. is currently with the University of New Mexico ( and the New Mexico VA Health Care System. J.D.P. is currently employed at Walter Reed Army Institute of Research (WRAIR). Material has been reviewed by WRAIR. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author (J.D.P.), and are not to be construed as official, or as reflecting true views of the Department of the Army of the Department of Defense. The animal studies were funded by NIH COBRE 2P20RR020145 (Ebersole, Project 5 RJD), NIH NINDS R01039041 (K.N.W.), VA Merit BX002695 (K.N.W.) and an institutional Wethington Award (K.N.W.). The mitochondrial work was supported by NIH grants NS062993 (P.G.S.) and NS069633 (P.G.S.). The authors declare no conflict of interest.

Reprints: Karin N. Westlund, PhD, Department of Anesthesiology & Critical Care Medicine, MSC10 6000, 2211 Lomas Blvd. NE, University of New Mexico School of Medicine, Albuquerque, NM 87131 (e-mail:

Received December 21, 2016

Received in revised form May 8, 2017

Accepted May 15, 2017

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