While there has been increasing recognition of the importance of microglial and astrocyte activation in the creation &maintenance of diverse enhanced pain states, an important aspect of glial functioning that has not yet been explored in the context of pain enhancement is the effect of a sensitized, or """"""""primed"""""""", microglial response. Evidence has accrued from outside of the pain field that the past history of microglial activation can dramatically alter their response to new challenges. Microglia can reach a primed state via a variety of challenges, including peripheral or central trauma/inflammation, stress, prior pain, and exposure to opioids, which strikingly are known co-morbidities for the transition of acute to chronic pain, including neuropathic pain. While in such a primed state, microglia now dramatically over-respond to new challenges, stronger and longer than before. We believe such prior challenges that result in glial priming can set the stage for the transition of acute to chronic pain following peripheral ¢ral neural damage, resulting in chronic neuropathic pain. Re-activation of primed microglia may lead to a transition from acute pain to chronic pain as a result of a neuroinflammatory response that is greatly amplified in both magnitude and duration. Goals. (1) In accordance with the specified goals of this RFA, develop new rat models to study the transition from acute to chronic neuropathic pain, based on the premise that a first challenge (Hit 1: peripheral or central trauma/inflammation, stress, prior pain, exposure to opioids) will markedly enhance pain induced by a subsequent (second) challenge (Hit 2: peripheral or central neural inflammation/injury). (2) Utilize the refined robust models to test the potential of non-opioid, non-addictive blood-brain barrier permeable glial activation inhibitors &resolvins to prevent the transition of acute to chronic pain. (3) Given the remarkably powerful positive effects produced by chronic voluntary exercise in creating resiliency to a multitude of negative outcomes (including constraining glial/immune reactivity), chronic voluntary exercise will also be tested for its ability to prevent the transition from acute to chronic pain, an approach enabled by teaming with an expert from outside the pain field (M. Fleshner). (4) Discover intracellular changes that differentiate rats which do vs. do not transition from acute to chronic neuropathic pain, &define how these potential cellular markers of impending chronic pain are affected by successful interventions (glial inhibitors, voluntary exercise). This will lay the groundwork for identifying and targeting changes reliably predictive of the transition of acute to chronic neuropathic pain.

Public Health Relevance

Neuropathic pain occurs in epidemic proportions worldwide, with little understanding of how and why the transition of acute-to-chronic pain occurs. This project explores the hypothesis that glial sensitization (priming) lies at the heart of the why acute pain can become chronic after peripheral or central neural damage. In addition, it explores two strategies - one pharmacological (drugs that inhibit glial activation;resolvins), one non-pharmacological (voluntary exercise prior to pain onset) - for preventing the evolution of chronic pain.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-B (51))
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Kusiak, John W
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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Lacagnina, Michael J; Watkins, Linda R; Grace, Peter M (2018) Toll-like receptors and their role in persistent pain. Pharmacol Ther 184:145-158
Grace, Peter M; Strand, Keith A; Galer, Erika L et al. (2018) MicroRNA-124 and microRNA-146a both attenuate persistent neuropathic pain induced by morphine in male rats. Brain Res 1692:9-11
Grace, Peter M; Wang, Xiaohui; Strand, Keith A et al. (2018) DREADDed microglia in pain: Implications for spinal inflammatory signaling in male rats. Exp Neurol 304:125-131
Grace, Peter M; Strand, Keith A; Galer, Erika L et al. (2018) Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in male rats. Brain Behav Immun 72:45-50
Spencer, Sarah J; D'Angelo, Heather; Soch, Alita et al. (2017) High-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory. Neurobiol Aging 58:88-101
Lewis, Susannah S; Grace, Peter M; Hutchinson, Mark R et al. (2017) Constriction of the buccal branch of the facial nerve produces unilateral craniofacial allodynia. Brain Behav Immun 64:59-64
Grace, Peter M; Loram, Lisa C; Christianson, John P et al. (2017) Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy. Brain Behav Immun 59:49-54
Sobesky, Julia L; D'Angelo, Heather M; Weber, Michael D et al. (2016) Glucocorticoids Mediate Short-Term High-Fat Diet Induction of Neuroinflammatory Priming, the NLRP3 Inflammasome, and the Danger Signal HMGB1. eNeuro 3:
Frank, Matthew G; Adhikary, Sweta; Sobesky, Julia L et al. (2016) The danger-associated molecular pattern HMGB1 mediates the neuroinflammatory effects of methamphetamine. Brain Behav Immun 51:99-108
Grace, Peter M; Gaudet, Andrew D; Staikopoulos, Vasiliki et al. (2016) Nitroxidative Signaling Mechanisms in Pathological Pain. Trends Neurosci 39:862-879

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