ENDOTHELIN 1 INDUCED PAIN AND METASTATIC PROSTATE CANCER

描述：（改编自申请人摘要） 疼痛是转移性前列腺癌的常见和致残性后果， 人类这种疼痛的原因尚不清楚，但很可能涉及 肿瘤细胞对脊神经根的介体依赖性信号传导。候选 一种强有力的血管收缩肽-内皮素-1（ET-1）， 在高浓度的转移性前列腺癌细胞中， 引起动物和人类疼痛。该提案旨在作为其广泛的 建立脊神经根痛的分子基础 因为前列腺癌转移初步研究表明，ET-1 应用于大鼠坐骨神经产生疼痛行为，即1）ETA 受体依赖性，和2）可能是由于对感觉传入的直接作用。 拟议研究的目标是联合收割机的体内结果 神经生理学和体外细胞生理学，以建立： 具体目标1：ET-1的作用或兴奋的选择性 功能鉴定的外周轴突 具体目标2：ET-1产生神经元的离子和细胞机制 激发 具体目标3：离子和细胞靶点的重要性， ET-1在体内诱导的疼痛行为 因此，这些实验的结果将确定ET-1在 转移性前列腺癌产生的疼痛，确定哪些感觉传入 介导ET-1诱导的疼痛，并分析离子和细胞机制， ET-1对感觉神经元的兴奋作用。这些信息应该 有助于确定：1）新的和有用的研究方向的机制 转移性前列腺癌引起的潜在疼痛，和2）新靶点 用于治疗这种疼痛的药物开发。

DESCRIPTION: (adapted from applicant's abstract) Pain is a frequent and disabling consequence of metastatic prostate cancer in humans. The cause of this pain is unknown, but is likely to involve mediator-dependent signaling by tumor cells to spinal nerve roots. A candidate mediator, the potent vasoconstrictive peptide endothelin-1 (ET-1), is secreted in high concentrations by metastatic prostate cancer cells and is known to induce pain in animals and in humans. This proposal seeks as its broad long-term objective to establish the molecular basis of spinal nerve root pain due to metastatic prostate cancer. Preliminary studies demonstrate that ET-1 applied to rat sciatic nerve produces pain behavior that is 1) ETA receptor-dependent, and 2) likely due to direct actions on sensory afferents. The goals of the proposed studies are to combine results from in vivo neurophysiology and in vitro cellular physiology in order to establish: Specific Aim 1: The selectivity of ET-1's actions or excitation of functionally-identified peripheral axons Specific Aim 2: the ionic and cellular mechanisms by which ET-1 produces neural excitation Specific Aim 3: The importance of ionic and cellular targets, identified in vitro, for ET-1 induced pain behavior in vivo The findings from these experiments will thus define a role for ET-1 in the pain produced by metastatic prostate cancer, identify which sensory afferents mediate ET-1 induced pain, and analyze the ionic and cellular mechanisms that underlie ET-1's excitatory effects on sensory neurons. This information should help to identify: 1) new and useful directions for research into the mechanisms underlying pain produced by metastatic prostate cancer, and 2) novel targets for drug development aimed at treating this pain.