New approaches for treating chronic pain are needed, particularly since existing analgesics have serious side effects and are not always effective at treating inflammatory pain and neuropathic pain-the two most common forms of chronic pain in humans. Inflammation and nerve injury lead to the release of a complex mix of chemicals that signal through molecularly diverse pronociceptive (pain-producing) receptors. Activation of these receptors increases the excitability and sensitivity of nociceptive dorsal root ganglia (DRG) and trigeminal ganglia neurons. Unfortunately, efforts to block individual pronociceptive receptors have so far failed to produce effective treatments for chronic pain. Here, we propose an innovative approach to reduce pain hypersensitivity that bypasses this long-standing problem associated with receptor diversity. Our approach is based on selectively reducing the level of the lipid second messenger phosphatidylinositol 4,5- bisphosphate (PIP2) in DRG neurons. Most pronociceptive receptors require PIP2 to initiate downstream signaling. Moreover, many TRP channels that detect noxious stimuli and ion channels that regulate membrane excitability require PIP2 for activity. PIP2 thus sits at a key convergence point for diverse receptors, ion channels and signaling pathways that promote and maintain chronic pain. In preliminary studies with mice, we identified a lipid kinase that generates at least 50% of all PIP2 in DRG neurons. Moreover, inactivation of this lipid kinase profoundly reduced nociceptive sensitization in response to an inflammatory agent. Based on our preliminary data, we hypothesize that this lipid kinase acts through PIP2 dependent mechanisms to regulate pronociceptive receptor signaling in DRG neurons and pain sensitization in vivo. To test this hypothesis we will: 1. Evaluate the extent to which this lipid kinase regulates nociceptive sensitization in vivo, using mouse models of acute, chronic and spontaneous pain, including models of inflammatory pain and neuropathic pain. We will use an innovative genetic approach to knock-down kinase activity. This approach selectively reduces PIP2 concentration in DRG but does not affect PIP2 concentration in other tissues that process pain signals. We will further evaluate PIP2-dependence using biochemical rescue experiments. 2. Evaluate the extent to which this kinase regulates signaling through diverse pronociceptive receptors, including G protein-coupled receptors, a tyrosine kinase receptor, and TRP channels that detect noxious stimuli. 3. Utilize a new conditional knockout mouse to inducibly delete this kinase only in sensory neurons of adults and to evaluate the extent to which this kinase regulates initiation and maintenance of inflammatory pain and neuropathic pain. We will be the first to rigorously study the importance of this kinase in the setting of chronic pain. Our preliminary data suggest this lipid kinase is a master regulator of pain signaling and sensitization.

Public Health Relevance

Existing analgesics like opioids have serious side effects when administered long-term, highlighting a major unmet medical need for new ways to treat chronic pain. Given that inactivation of this lipid kinase reduces symptoms of chronic pain in mammalian models, inhibitors of this lipid kinase could have powerful analgesic properties in humans. Kinases are druggable targets, so completion of our research could lead to future development of a new class of powerful, non-opioid-based analgesics.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Porter, Linda L
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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McCoy, Eric S; Zylka, Mark J (2014) Enhanced behavioral responses to cold stimuli following CGRP? sensory neuron ablation are dependent on TRPM8. Mol Pain 10:69
Rittiner, Joseph E; Brings, Victoria E; Zylka, Mark J (2014) Overexpression of diacylglycerol kinase ? enhances G?q-coupled G protein-coupled receptor signaling. Mol Pharmacol 85:800-10
Wright, Brittany D; Loo, Lipin; Street, Sarah E et al. (2014) The lipid kinase PIP5K1C regulates pain signaling and sensitization. Neuron 82:836-47