Endothelin mechanisms in metastatic prostate cancer pain

描述(由申请人提供)：疼痛是人类转移性癌症的一种常见和致残的后果。这种疼痛的原因尚不清楚，但可能涉及肿瘤细胞向伤害性感受器传递依赖于介体的信号。强大的血管活性多肽，内皮素-1(ET-1)，由转移性癌细胞分泌高浓度，在动物和人类中产生疼痛。这项提案寻求将了解肿瘤介质如何引起与癌症相关的疼痛作为其广泛的长期目标。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性感受器兴奋，2)介导皮肤损伤和炎症的啮齿动物模型的机械性和热敏性痛觉过敏，3)通过ETA引起钙离子增加，并通过ETA在分离的感觉神经元上开放河豚毒素抗性(TTX-R)Na+通道，3)通过ETB受体在皮肤中触发止痛级联反应，这是通过局部释放的β-内啡肽作用于与G蛋白内向整流钾通道(GIRKs)耦合的阿片受体而介导的。拟议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相结合，以：具体目标： 1：确定ET-1在外周伤害性感受器中启动冲动，并确定这种冲动启动背后的离子(Na+和K+)电流的变化。具体目标2：建立ET-1使外周伤害性感受器对注射去极化电流以及辣椒素和ATP的去极化作用敏感。具体目标3：确定β-内啡肽抑制ET-1引起的伤害性感受器兴奋性改变的离子基础。这些实验的发现将确定ET-1向伤害性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内啡肽介导的抑制ET-1触发的疼痛的离子机制。这些信息应该有助于确定：1)研究转移性癌症产生疼痛的潜在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。

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.