Neural Mechanisms of Cancer Pain

癌痛的神经机制

• 批准号: 10171566
• 负责人: Donald Simone
• 金额: $ 37.82万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171566
• 关键词: Acute; Address; Adult; Affect; Afferent Neurons; Attenuated; Behavior; Binding; Biochemical; Biological Assay; Bone Pain; C Fiber; C3H/HeN Mouse; Calcium; Caliber; Cancer Pain Management; Capsaicin; Cells; Chemicals; Complex; Conditioned Culture Media; Data; Development; Dose; Drug resistance; Electrophysiology (science); Enzymes; Female; Future; Genes; Goals; Hyperalgesia; In Vitro; Inflammatory; Injections; Lysophosphatidic Acid Receptors; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measures; Mechanics; Mediating; Mental Health; Metastatic Neoplasm to the Bone; Molecular; Morbidity - disease rate; Mus; Neoplasm Metastasis; Neurons; Neuropathy; Nociception; Nociceptors; Omega-3 Fatty Acids; Osteolytic; Pain; Pathway interactions; Patients; Pharmacology; Physiological; Play; Quality of life; Research; Role; Signal Transduction; Small Interfering RNA; Spinal Ganglia; Stimulus; Testing; Thermal Hyperalgesias; Time; angiogenesis; cancer cell; cancer pain; cancer therapy; efficacious treatment; exosome; experimental study; extracellular; fibrosarcoma; in vivo; inhibitor/antagonist; insight; knock-down; lysophosphatidic acid; male; malignant breast neoplasm; nanoparticle; nanovesicle; neuromechanism; novel strategies; painful neuropathy; protein biomarkers; protein expression; receptive field; response; sex; spinal nerve posterior root; tumor growth; tumor progression; tumorigenesis; tumorigenic; vzg-1 Receptor

ABSTRACT The management of cancer pain remains a major challenge. Cancer pain is a complex pain state that includes inflammatory, neuropathic components and a unique set of cancer-specific components. Exosomes secreted by cancer cells is one of those cancer-specific factors. In preliminary studies, exosomes confirmed by size and expression of protein markers, induced acute mechanical and heat hyperalgesia following injection into the hind paw of both sexes of naïve C3H/HeN mice. This project will test the hypothesis that exosomes secreted by fibrosarcoma cells produce pain by sensitizing nociceptive primary afferent neurons via the autotaxin (ATX)-lysophosphatidic acid (LPA)-LPA1 receptor (R) pathway. Exosomes isolated from fibrosarcoma cell-conditioned media will be verified by size (Nanoparticle tracking analysis), expression of the exosome-specific markers, and activity of ATX. Electrophysiological studies in vivo will determine the contribution of ATX-LPA-LPA1R signaling to exosome-specific sensitization of nociceptors. At the cellular level, acute sensitization of small dorsal root ganglion (DRG) neurons from adult mice will be defined in a bioassay that measures the occurrence of a calcium transient in response to depolarization with 25 mM KCl in vitro with Indo-1. Whether the exosome-bound ATX-LPA complex released from fibrosarcoma cells sensitizes DRG neurons through activation of LPA1 receptors will be determined using pharmacological and molecular (siRNA) approaches. Resolvin D1 is proposed to attenuate exosome-evoked sensitization of nociceptors and hyperalgesia by interfering with ATX-LPA- LPA1R signaling. If exosome-mediated ATX-LPA-LPA1R signaling underlies hyperalgesia, it will provide insight into a new strategy for managing bone cancer pain. Future studies will further investigate the molecular, biochemical and electrophysiological mechanisms by which exosomes released from cancer cells contribute to cancer pain.

抽象的 癌症疼痛的管理仍然是一个重大挑战。癌症疼痛是一种复杂的疼痛 包括炎症性，神经性成分和一组独特的癌症特异性的状态 成分。癌细胞分泌的外泌体是癌症特异性因素之一。在 初步研究，通过蛋白质标记的大小和表达证实的外泌体，诱导 注射到两性的后爪之后，急性机械和热痛觉过敏 幼稚的C3H/母鸡小鼠。该项目将检验以下假设 纤维肉瘤细胞通过通过敏化伤害性一级传入神经元来产生疼痛 自型（ATX） - 溶质磷脂酸（LPA）-LPA1受体（R）途径。外泌体分离 通过纤维肉瘤细胞调节培养基的大小将验证（纳米颗粒跟踪 分析），外泌体特异性标记的表达和ATX活性。电生理学 体内研究将确定AT​​X-LPA-LPA1R信号对外泌体特异性的贡献 伤害感受器的敏化。在细胞水平，小背根的急性灵敏度 来自成年小鼠的神经元（DRG）神经元将在生物测定中定义，以测量 钙瞬态响应于25 mM KCL的体外沉积而发生 Indo-1。是否从纤维肉瘤细胞释放出外泌体的ATX-LPA复合物是否 通过激活LPA1受体的感觉DRG神经元将使用 药理和分子（siRNA）接近。提议溶质D1衰减 通过干扰ATX-LPA-的外部诱发的伤害感受器和痛觉过敏的敏感性 LPA1R信号传导。如果外泌体介导的ATX-LPA-LPA1R信号传导是Hypergensia的基础，它将 提供有关管理骨癌疼痛的新策略的洞察力。未来的研究将进一步 研究分子，生化和电生理机制 癌细胞释放的外泌体有助于癌症疼痛。