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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
The Clinical Journal of Pain: Post Acceptance: May 24, 2017
doi: 10.1097/AJP.0000000000000515
Original Article: PDF Only


The study aim was to determine how peripheral trigeminal nerve injury affects mitochondrial respiration and to test efficacy of combined treatment with two FDA approved drugs with potential for improving mitochondrial bioenergetics, pain and anxiety related behaviors in a chronic orofacial neuropathic pain mouse model.


Efficacy of (R)-(+)-4-amino-3-isoxazolidinone (D-cycloserine, DCS), an NMDA antagonist/agonist, and Pioglitazone (PIO), a selective agonist of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) 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. Additionally, beneficial effects of the DCS/PIO drug combination were explored ex-vivo in isolated cortex/brainstem mitochondria at 28 weeks post-TIC.


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.


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 suffering from depression, anxiety, or other psychological conditions due to their chronic pain status.

Jignesh D. Pandya; Present Address: 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.

The authors declare no conflict of interest.

Reprints: Karin N. Westlund, PhD, Department of Physiology MS-508, College of Medicine, University of Kentucky, Lexington, KY 40536-0298 (e-mail:

Received December 21, 2016

Accepted May 15, 2017

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