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: 7104354
• 负责人: GARY R STRICHARTZ
• 金额: $ 40.9万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104354
• 关键词: adenosine triphosphate; cancer pain; capsaicin; electrodes; endorphins; endothelin; gene targeting; genetically modified animals; hormone regulation /control mechanism; laboratory mouse; laboratory rat; metastasis; neural conduction; neuropsychological tests; nociceptors; potassium channel; prostate neoplasms; receptor expression; receptor sensitivity; sodium channel; voltage /patch 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和致残性后果。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体依赖性信号传导。转移性癌细胞分泌高浓度的强效血管活性肽内皮素-1（ET-1），并在动物和人类中产生疼痛。该提案寻求其广泛的长期目标，以了解肿瘤介质如何引起与癌症相关的疼痛。我们已经证明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Cain 2+增加，并在分离的感觉神经元中打开河豚毒素抗性（TTX-R）Na+通道，3）通过ETB受体触发皮肤中的镇痛级联反应，它是由局部释放的β-内啡肽作用于阿片受体介导的，阿片受体与G蛋白内向整流K+通道（GIRKs）偶联。拟定研究的目标是将体外神经生理学和药理学的结果与神经行为联合收割机结合起来，以： 一曰：确定ET-1在外周伤害感受器中启动脉冲，并确定作为该脉冲启动基础的离子（Na+和K+）电流的变化。具体目标二：确定ET-1使外周伤害感受器对去极化电流的注射以及对辣椒素和ATP的去极化作用都敏感。具体目标3：确定β-内啡肽对ET-1诱导的伤害感受器兴奋性变化的抑制作用的离子基础。来自这些实验的发现将定义ET-1向伤害感受器发出信号以引起急性和持续性疼痛的离子机制，以及ETB驱动的β内啡肽介导的ET-1触发的疼痛的抑制作用的离子机制。这些信息应该有助于确定：1）研究转移性癌症产生疼痛的机制的新的和有用的方向，以及2）旨在治疗这种疼痛的药物开发的新靶点。