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.
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.
|Ellis, Amanda; Grace, Peter M; Wieseler, Julie et al. (2016) Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury. Brain Behav Immun 58:348-356|
|Grace, Peter M; Fabisiak, Timothy J; Green-Fulgham, Suzanne M et al. (2016) Prior voluntary wheel running attenuates neuropathic pain. Pain 157:2012-23|
|Grace, Peter M; Strand, Keith A; Galer, Erika L et al. (2016) Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A 113:E3441-50|
|Grace, Peter M; Gaudet, Andrew D; Staikopoulos, Vasiliki et al. (2016) Nitroxidative Signaling Mechanisms in Pathological Pain. Trends Neurosci 39:862-879|
|Fonken, Laura K; Kitt, Meagan M; Gaudet, Andrew D et al. (2016) Diminished circadian rhythms in hippocampal microglia may contribute to age-related neuroinflammatory sensitization. Neurobiol Aging 47:102-112|
|Wang, X; Zhang, Y; Peng, Y et al. (2016) Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4. Br J Pharmacol 173:856-69|
|Dodds, K N; Beckett, E A H; Evans, S F et al. (2016) Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain. Transl Psychiatry 6:e888|
|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|
|Kwilasz, A J; Grace, P M; Serbedzija, P et al. (2015) The therapeutic potential of interleukin-10 in neuroimmune diseases. Neuropharmacology 96:55-69|
|Bachtell, Ryan; Hutchinson, Mark R; Wang, Xiaohui et al. (2015) Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4. CNS Neurol Disord Drug Targets 14:692-9|
Showing the most recent 10 out of 38 publications