Chronic Intermittent Hypoxia and Hyperalgesic Priming

PROJECT SUMMARY Sleep is critical to health and well-being, such that current trends towards reduced sleep time and quality, coupled with rising diagnoses of sleep disorders, negatively affect multiple physiological systems. Increasing clinical evidence indicates that sleep disorders such as obstructive sleep apnea (OSA) contribute to chronic pain, with over 40% of sleep disordered patients reporting chronic pain conditions. However, there is a gap in knowledge concerning how disorders such as intermittent hypoxia contribute to persistent pain. Our long-term goal is to reduce persistent pain in patients experiencing sleep disorders. As we work towards this goal, the overall objective of this application is to define the mechanism by which intermittent hypoxia contributes to the transition from acute-to-chronic pain. Our central hypothesis is that hypoxia from sleep disorders produces neuroimmune hyperalgesic priming via peripheral macrophage up-regulation. We propose that chronic intermittent hypoxia stimulates macrophage polarization to increase inflammatory cytokine production in peripheral nociceptive tissues. Our hypothesis is based on strong evidence utilizing an innovative rodent model for chronic intermittent hypoxia (CIH) that mimics OSA. The rationale for this work is that increasing our mechanistic understanding of how intermittent hypoxia contributes to persistent pain could improve quality of life for tens of millions of American that suffer from sleep disorders. To accomplish our objective, we will test our central hypothesis with the following related, yet interdependent aims: (1) Identify the location of neuroimmune interaction, (2) Interrogate the distribution and role of M1/M2 macrophage polarization, and (3) Examine hypoxic activation of peripheral macrophages. We propose a multi-disciplinary approach to testing our hypothesis, utilizing transgenic and Cre-Lox recombination mice in biochemical, pharmacological, in vivo imaging and behavioral protocols with FACS cell sorting and RNA profiling in tandem. Our CIH treatment paradigm is highly innovative for its translational relevance to human OSA, as is our molecular and biochemical profiling of resident and infiltrating macrophage populations in hyperalgesic priming. The proposed research is significant because it will identify novel mechanisms by which sleeping disorders contribute to persistent pain.