从急性疼痛到慢性疼痛转变中的趋化因子信号传导-猫眼课题宝

从急性疼痛到慢性疼痛转变中的趋化因子信号传导

批准号：

8634938

负责人：

FLETCHER A WHITE

金额：

$0.0万

依托单位：

RLR VA MEDICAL CENTER

依托单位国家：

美国

项目类别：

财政年份：

2014

资助国家：

美国

项目状态：

已结题

起止时间：

2014-01-01 至 2017-12-31

来源：

https://reporter.nih.gov/project-details/8634938

关键词：

AMD3100 Acute Acute Pain Adverse effects Affect Afferent Neurons Analgesics Animals Antibodies Anxiety Area Behavioral Behavioral Assay CXCL12 gene CXCR4 Receptors CXCR4 gene Calcium Cells Chimeric Proteins Chronic Clinical Data Development Disease Exhibits FDA approved Fright Functional disorder Goals Hippocampus (Brain)Inflammatory Injury Knock-out Lead Learning Life Ligands Link Location Maintenance Mediating Memory Mental Depression Methods Modeling Modification Molecular Motor Activity Mus Nature Nerve Nervous System Trauma Nervous system structure Neuroglia Neurons Nociception Pain Pain Disorder Pain Threshold Pathway interactions Peripheral nerve injury Phenotype Physicians Population Production Protocols documentation Quality of life Rattus Reagent Receptor Signaling Regulation Reporter Research Rodent Rodent Model Role Signal Transduction Societies Sodium Spinal Cord Spinal Ganglia Stromal Cell-Derived Factor 1 Structure of tibial nerve Substance abuse problem Syndrome Tactile Hyperalgesias Testing Therapeutic Time Transcript Transgenic Mice Transgenic Organisms Veterans Vulnerable Populations Work behavior change chemokine chemokine receptor chronic neuropathic pain chronic pain cytokine density design effective therapy experience injured insight interest migration nerve injury neuronal excitability new therapeutic target novel pain behavior painful neuropathy public health relevance receptor research study tool voltage voltage clamp

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The goal of this proposal is to demonstrate the importance of the chemokine/chemokine receptor signaling by stromal derived factor 1 alpha (SDF1; also known as CXCL12) and its cognate receptor CXCR4 in rodent models of neuropathic pain. Dysregulated expression chemokine receptors have been linked to hyperexcitability of dorsal root ganglia (DRG) neurons which underlies peripherally-originated neuropathic pain and constitutes a large number of neuropathic pain disorders. The studies described in this application are designed to fill the gap in our understanding of how nerve injury-induced excitatory changes in SDF1/CXCR4 signaling contribute to the persistence of chronic neuropathic pain. Our preliminary data shows that CXCR4 is absent from sensory neurons in the DRG and are generally unresponsive to SDF1. Studies in our lab have shown that injury substantially enhances both levels of CXCR4 transcripts in DRG and sensory neuron expression of CXCR4 in transgenic reporter mice. Further evidence suggests that this injury-mediated modulation of CXCR4 may also contribute to altered neuronal hyperexcitability. In this proposal, we will carry out studies of injury-mediated effects on pain thresholds and hyperexcitability at the cellular level in DRG neurons using the FDA-approved highly specific CXCR4 receptor antagonist to test the hypotheses that: i) Block of CXCR4 in DRG neurons derived from injured rodents ameliorates pain behavior; ii) Injury alters calcium or sodium currents in CXCR4 responsive nociceptive DRG neurons; iii) Modulation of SDF1/CXCR4 signaling may serve as a molecular switch to a chronic pain state. We will also use molecular and immunological methods, and voltage-clamp and current-clamp recordings to: iv) Assess injury-mediated effects on altered regulation of expression and modulation of CXCR4; and v) Correlate changes at the molecular and cellular levels in injured and adjacent, uninjured DRG neurons to changes in pain thresholds.

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