Endothelin mechanisms in metastatic prostate cancer pain

内皮素在转移性前列腺癌疼痛中的作用机制

• 批准号: 7409637
• 负责人: GARY R STRICHARTZ
• 金额: $ 39.71万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-16 至 2009-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409637
• 关键词: Absence of pain sensation; Action Potentials; Acute; Acute Pain; Afferent Neurons; Analgesics; Animals; Behavior; Bite; Breast; CALCA gene; Calcitonin Gene-Related Peptide; Calcium; Capsaicin; Cells; Cervical; Chemicals; Dependence; Dinoprostone; Disseminated Malignant Neoplasm; Electrodes; Endorphins; Endothelin; Endothelin A Receptor; Endothelin B Receptor; Endothelin-1; Exposure to; Fire - disasters; Formalin; Frequencies; GIRK2 subunit, G protein-coupled inwardly-rectifying potassium channel; GTP-Binding Proteins; Goals; Growth; Human; In Vitro; Inflammation; Injection of therapeutic agent; Injury; Ion Channel; Kinetics; Knockout Mice; Malignant Neoplasms; Measures; Mechanics; Mediating; Mediator of activation protein; Metastatic Prostate Cancer; Methods; Mitogens; Movement; Mus; Neonatal; Neurons; Nociceptors; Opioid; Opioid Receptor; Ovarian; Pain; Pathogenesis; Pathway interactions; Patients; Pattern; Peptides; Peripheral; Persistent pain; Pharmacology; Potassium Channel; Preparation; Prostate; Protein Isoforms; Rattus; Recovery; Research; Resistance; Rodent Model; Role; S100A12 gene; Sensory; Signal Transduction; Skin; Slice; Sodium Channel; Spinal Ganglia; Stimulus; Substance P; Surgical incisions; Testing; Tetrodotoxin; Thermal Hyperalgesias; Tumor Tissue; Whole-Cell Recordings; Withdrawal; base; beta-Endorphin; cancer cell; cancer pain; drug development; girls; human S100A12 protein; in vivo; indium arsenide; inward rectifier potassium channel; neoplastic cell; nerve injury; neurobehavior; neurobehavioral; neuronal cell body; neurophysiology; novel; receptor; receptor coupling; research study; response; spontaneous pain; tumor; voltage; voltage clamp

DESCRIPTION (provided by applicant): Pain is a frequent and disabling consequence of metastatic cancer in humans. The cause of this pain is unknown but likely to involve mediator-dependent signaling by tumor cells to nociceptors. The potent vasoactive peptide, endothelin-1 (ET-1), is secreted in high concentrations by metastatic cancer cells and produces pain in animals and in humans. This proposal seeks as its broad long-term objective to understand how tumor mediators cause pain associated with cancer. We have shown that ET-1: 1) induces acute pain behavior and nociceptor excitation via endothelin-A receptors (ETA), 2) mediates mechanical and thermal hyperalgesia in rodent models of skin injury and inflammation, 3) evokes increased Cain2+ , and opening of tetrodotoxin-resistant (TTX-R) Na+ channels in isolated sensory neurons, via ETA, 3) triggers an analgesic cascade in skin, via ETB receptors, that is mediated by locally-released beta-endorphin acting on opioid receptors coupled to G protein inwardly-rectifying K+ channels (GIRKs). The goals of the proposed studies are to combine results from in vitro neurophysiology and pharmacology with neurobehavior to: Specific Aim: 1: Establish that ET-1 initiates impulses in peripheral nociceptors, and identify the changes in ionic (Na+ and K+) currents that underlie this impulse initiation. Specific Aim 2: Establish that ET-1 sensitizes peripheral nociceptors both to the injection of depolarizing current and to the depolarizing actions of both capsaicin and ATP. Specific Aim 3: Determine the ionic basis for inhibitory effects of beta-endorphin on ET-1-induced changes in nociceptor excitability. The findings from these experiments will define the ionic mechanisms whereby ET-1 signals to nociceptors to cause acute and persistent pain, and the ionic mechanisms that underlie inhibitory effects of ETB driven, beta endorphin-mediated inhibition of ET-1-triggered pain. This information should help to identify: 1) new and useful directions for research into mechanisms underlying pain produced by metastatic cancer, and 2) novel targets for drug development aimed at treating this pain.

描述（由申请人提供）：疼痛是人类转移性癌症的常见致残后果。这种疼痛的原因尚不清楚，但可能涉及肿瘤细胞对伤害感受器的介质依赖性信号。强效的血管活性肽内皮素-1 （ET-1）由转移性癌细胞高浓度分泌，在动物和人类中产生疼痛。该建议寻求作为其广泛的长期目标，了解肿瘤介质如何引起与癌症相关的疼痛。我们已经证明了ET-1：1)通过内皮素a受体（ETA）诱导急性疼痛行为和伤害感受器兴奋，2)在皮肤损伤和炎症的啮齿动物模型中介导机械和热痛觉过敏，3)通过ETA引起Cain2+的增加，并在孤立的感觉神经元中打开河狸毒素抗性（TTX-R） Na+通道，3)通过ETB受体在皮肤中触发镇痛级联，这是由局部释放的内啡肽介导的，它作用于与G蛋白向内校正K+通道（GIRKs）偶联的阿片受体。拟议研究的目标是将体外神经生理学和药理学与神经行为学的结果结合起来，以达到：