Biochemical Modulation of Nociceptive Circuits

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DESCRIPTION (provided by applicant): Neuropathic pain is a chronic and debilitating disease that is difficult to treat with existing analgesics. Recent studies reveal a critical role for lysophosphatidic acid (LPA) receptor activation in causing neuropathic pain. We found that many small diameter, presumably nociceptive, dorsal root ganglia (DRG) and trigeminal neurons express a transmembrane-localized phosphatase that dephosphorylates LPA. Based on these observations, our long term research objectives are to demonstrate that this phosphatase modulates LPA receptor signaling in vitro, using cultured sensory neurons, and in vivo, using mouse neuropathic pain models. To accomplish this, we will first use immunohistochemistry to characterize the sensory neurons that express this phosphatase and identify the peripheral tissues that are innervated by phosphatase-containing afferents. Next, we will test the hypothesis that this phosphatase modulates LPA receptor signaling in cell lines and in dissociated mouse DRG neurons using calcium imaging and luciferase reporter gene assays. We will use genetically modified mice expressing Green Fluorescent Protein to identify the DRG neurons that express this phosphatase. Finally, we will test the hypothesis that this phosphatase modulates neuropathic pain behaviors in wild-type and phosphatase knockout mice.