ENDOTHELIN 1 INDUCED PAIN AND METASTATIC PROSTATE CANCER

描述：(改编自申请者摘要) 疼痛是转移性前列腺癌的常见和致残后果。 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。一位候选人 内皮素-1(ET-1)是一种有效的血管收缩多肽，它被分泌出来 在转移性前列腺癌细胞中的高浓度，并已知 在动物和人类身上引起疼痛。这项建议寻求其广泛的 长期目标：建立脊神经根性疼痛的分子基础 由于转移性前列腺癌。初步研究表明，ET-1 应用于大鼠坐骨神经会产生疼痛行为，即1)ETA 受体依赖，以及2)可能是由于对感觉传入的直接作用。 拟议研究的目标是将活体研究的结果结合起来 神经生理学和体外细胞生理学，以确定： 具体目标1：ET-1‘S作用或兴奋的选择性 功能识别的外周轴突 特定目标2：ET-1产生神经的离子和细胞机制 激励 具体目标3：离子和细胞目标的重要性，确定于 体外，用于ET-1诱导的体内疼痛行为 因此，这些实验的发现将确定ET-1在 转移性前列腺癌引起的疼痛，确定哪些感觉传入 介导ET-1诱导的疼痛，并分析其离子和细胞机制 ET-1‘S对感觉神经元的兴奋作用。此信息应为 有助于确定：1)机制研究的新的和有用的方向 转移性前列腺癌引起的潜在疼痛，以及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.