Veterans have more severe chronic pain than non-veteran patients and are reportedly twice as likely to die of an opioid overdose in attempts to find relief. These consequences lie behind the critical need to determine brain alterations causing chronification of pain that are too often progressing to the anxiety and depression responsible for the increased suicide rate among our veterans. Better understanding of underlying mechanisms driving chronic pain is imperative to development of more effective non-opioid treatment approaches for chronic pain. During the currently funded VA Merit grant period, we performed manganese enhanced MRI (MEMRI) studies using our experimental chronic neuropathic pain model. MEMRI allows visualization of neural activation in the small rodent brain using a 7T Bruker MRI scanner. As in clinical fMRI studies, we identified specific limbic emotional brain regions overactivated by chronic pain in addition to activation of the pain circuitry itself. It is apparent in our Preliminary Data histological follow-up that ongoing cellular stress is occurring in limbic brain circuitry. Due to the neuronal overactivation, pathophysiological alterations in limbic brain pain circuitry include increased expression of cellular stress biomarkers and altered expression of protective autophagy biomarkers. Autophagy is defined as the ongoing cellular protective mechanisms removing damaged and misfolded proteins generated during cellular stress. Disrupted autophagy homeostasis that produces autophagic dysfunction adversely affects cell function and eventually viability. The goal of the proposed studies is to examine whether boosting cell protective autophagy mechanisms can not only reduce neuropathic pain chronification related behaviors but can conceivably reduce the related brain pain circuitry neuropathology. Our studies performed at 8-10 weeks after induction in our chronic neuropathic pain model allows salient clinical relevance. We will test whether cellular stress/autophagy mechanisms are related to the noradrenergic alpha 1 receptor (NA?1R) signaling we identified as a primary chronic pain generator in the previous Merit grant funding period. The NA?1R blocker we will test is the clinical therapeutic doxazosin that might also be used as PTSD therapy. Doxazosin is longer lasting than the prazosin we tested in the same model in the previous grant period. Prazosin reduced chronic pain and aversive anxiety and depression related behaviors we observed through the 10 week time points (see Progress Report). We will test efficacy of doxazosin to reduce chronic neuropathic pain induced mechanical hypersensitivity, and perform anxiety and depression related behavioral assays. Comparisons of the efficacy of doxazosin can be made to prazosin and the effects of cellular stress inhibitors/autophagy enhancers. We find based on our recently completed MEMRI study that overactivation in specific limbic cortical regions after 10 weeks of ongoing neuropathic pain results in altered cellular stress/autophagy biomarker expression that accompanies the chronic pain related behaviors.
The Aims proposed in this VA Merit renewal application include identification/validation of the cellular stress/autophagy RNA/protein expression signature in the chronic pain model at 10 weeks. Pilot efficacy testing of a cellular stress signaling pathway inhibitor and protective autophagy promotor finds reversal of chronic pain behaviors. Enhancement of protective autophagy mechanisms as defense against cellular stress and disrupted cellular homeostasis will be further demonstrated by quantifying oxidative stress/autophagy RNA, proteins, and other neuropathology as readouts. Imaging the distribution of inflammatory biomarker cathepsin B over time in live animals with whole body IVIS fluorescent infrared imaging will be a readout of the inflammatory component in peripheral and central nervous system. Completion of our assessment of the efficacy of these treatments to provide enhancement of protective autophagy mechanisms during chronic pain as defense against cellular stress and chronic pain related behaviors will increase the understanding of the chronification of neuropathic pain. Improved understanding will lead to better non-opioid treatments for chronic pain that provide better outcomes for veterans living with chronic pain.

Public Health Relevance

The overall goal of the proposed Merit renewal studies is to improve management of chronic nerve injury pain suffered by many veterans after blast, vehicular accident, and other combat injuries. Chronic head and neck pain are chief complaints of approximately 772,000 of the 2.5 million military personnel deployed since 2001 seeking care in the VA health care system. A clinically relevant experimental model of chronic pain is used to provide information not attainable with acute models including anxiety and depression measures that can accompany chronic pain. The central pain generator identified in the previous grant period driving intense activation of the nervous system during chronic pain also drives the appearance of cellular oxidative stress and damage proteins. This indicates restorative processes that protect cellular function are compromised in the pain processing circuitry. Proposed studies will test efficacy of oxidative stress inhibitors and enhancement of cellular protection mechanisms as means to limit effects of chronic pain.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Albuquerque VA Medical Center
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Danaher, Robert J; Zhang, Liping; Donley, Connor J et al. (2018) Histone deacetylase inhibitors prevent persistent hypersensitivity in an orofacial neuropathic pain model. Mol Pain 14:1744806918796763
Lyons, Danielle N; Zhang, Liping; Pandya, Jignesh D et al. (2018) Combination Drug Therapy of Pioglitazone and D-cycloserine Attenuates Chronic Orofacial Neuropathic Pain and Anxiety by Improving Mitochondrial Function Following Trigeminal Nerve Injury. Clin J Pain 34:168-177
Lyons, Danielle N; Zhang, Liping; Danaher, Robert J et al. (2017) PPAR? Agonists Attenuate Trigeminal Neuropathic Pain. Clin J Pain 33:1071-1080
McIlwrath, S L; Nesemeier, R; Ma, F et al. (2017) Inflammatory 'double hit' model of temporomandibular joint disorder with elevated CCL2, CXCL9, CXCL10, RANTES and behavioural hypersensitivity in TNFR1/R2-/- mice. Eur J Pain 21:1209-1223
Hansen, Barbara C; Gografe, Sylvia; Pritt, Stacy et al. (2017) Ensuring due process in the IACUC and animal welfare setting: considerations in developing noncompliance policies and procedures for institutional animal care and use committees and institutional officials. FASEB J 31:4216-4225
Taylor, Bradley K; Westlund, Karin N (2017) The noradrenergic locus coeruleus as a chronic pain generator. J Neurosci Res 95:1336-1346
Ma, Fei; Wang, Chunmei; Yoder, William E et al. (2016) Efficacy of Herpes Simplex Virus Vector Encoding the Human Preproenkephalin Gene for Treatment of Facial Pain in Mice. J Oral Facial Pain Headache 30:42-50
Kaushal, R; Taylor, B K; Jamal, A B et al. (2016) GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NA?1 receptors in the medial prefrontal cortex. Neuroscience 334:148-159
Ma, F; Zhang, L; Oz, H S et al. (2015) Dysregulated TNF? promotes cytokine proteome profile increases and bilateral orofacial hypersensitivity. Neuroscience 300:493-507
Lyons, D N; Kniffin, T C; Zhang, L P et al. (2015) Trigeminal Inflammatory Compression (TIC) injury induces chronic facial pain and susceptibility to anxiety-related behaviors. Neuroscience 295:126-38

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