Astrocyte Calcium Signaling in Neuropathic Pain

神经性疼痛中的星形胶质细胞钙信号传导

• 批准号: 10311988
• 负责人: Nicholas Alan Nelson
• 金额: $ 4.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311988
• 关键词: Acute; Acute Pain; Affect; American; Analgesics; Anatomy; Anesthetics; Animal Behavior; Animal Model; Arthritis; Astrocytes; Attention; Basic Science; Behavioral; Behavioral Assay; Brain; Ca(2+)-Transporting ATPase; Calcium; Calcium Signaling; Caring; Cell membrane; Data; Dependence; Development; Disease; Education; Electrophysiology (science); Esthesia; Gene Expression; Genetic; Genetic study; Hypersensitivity; Imaging Techniques; Immune response; Immunohistochemistry; Inflammatory Response; Institute of Medicine (U.S.); Intervention; Knowledge; Ligation; Malignant Neoplasms; Mammals; Measurement; Mechanics; Mechanoreceptors; Mediating; Methods; Modeling; Molecular; Morphology; Mus; Nerve; Nervous System Physiology; Neuraxis; Neuroglia; Neurons; Nociception; Nociceptors; Organ; Pain; Pain Disorder; Pain Research; Pain management; Pathogenesis; Pathway interactions; Pattern; Peripheral; Persistent pain; Pharmacology; Pharmacology Study; Photons; Physiological; Play; Posterior Horn Cells; Pre-Clinical Model; Process; Publishing; Reporting; Reproducibility; Research; Resolution; Role; Sensory; Signal Transduction; Site; Skin; Spinal; Spinal Cord; Spinal cord injury; Spinal cord posterior horn; Techniques; Tissues; Translating; Translations; Work; addiction; base; cell type; central sensitization; chronic pain; dorsal horn; effective therapy; experimental study; histological studies; imaging approach; improved; in vivo calcium imaging; insight; knock-down; miniaturize; nerve injury; novel; optogenetics; pain behavior; pain chronification; pain signal; painful neuropathy; phase change; pre-clinical; prevent; rational design; receptor; response; sciatic nerve; sensory integration; sex; side effect; spatiotemporal; temporal measurement; transcriptome; transcriptome sequencing; two-photon

PROJECT SUMMARY Chronic pain is a hallmark of many disease conditions, including nerve and spinal cord injury. Current mainstays of pain management include analgesics and anesthetics, treatments that are used despite their uncertain efficacy and known side effects. Safer and more productive approaches for pain management are urgently needed, but knowledge gaps in basic research have hampered the development and translation of novel treatments. To accelerate this process an improved understanding of the cellular and molecular basis of pain signaling is required. The spinal cord is a crucial signaling hub involved in communicating pain-related signals between peripheral organs and the brain. As the first site of sensory integration within the central nervous system (CNS), it plays essential roles in central sensitization. Much attention has focused on the neuronal cell types and circuits that contribute to this process. However, considerably less is known about the contributions of non-neuronal cells, such as astrocytes. While morphological changes in spinal astrocytes in relation to onset and progression of chronic pain have been well characterized, little is known about their dynamic activity patterns and how they relate to neuronal spiking or sex-specific immune responses. Historically, technical challenges have prevented such measurements in preclinical animal models under naturalistic conditions. The recent development of two-photon and miniaturized one-photon imaging approaches has enabled real-time measurement of cellular calcium activity in behaving mammals. This has provided first insights into how sensory information from mechanoreceptors and nociceptors in the skin acutely activates dorsal horn neurons and astrocytes. Using these cutting-edge imaging approaches in combination with computational, genetic, and behavioral techniques, the objective of this proposal is to define how astrocyte calcium activity changes in relation to neuropathic pain onset and progression, how its targeted manipulation influences neuronal and non-neuronal responses, and how it alters molecular signaling and animal behavior. The rationale for the proposed research is that by uncovering cellular and molecular mechanisms that contribute to pain onset or progression, new analgesic interventions can be devised. Three specific aims will be pursued: 1) Determine how astrocyte calcium excitation relates to neuropathic pain under naturalistic conditions; 2) Determine how inhibition of astrocyte calcium excitation modulates normal and aberrant sensory processing, and 3) Determine molecular pathways involved in astrocyte calcium excitation-mediated modulation of normal and aberrant sensory processing. In summary, this work will uncover how changes in astrocyte activity contribute to neuropathic pain on molecular, cellular, and behavioral levels. It will extend current models of how non-neuronal cells contribute to persistent pain specifically and CNS function broadly.

项目总结 慢性疼痛是许多疾病的标志，包括神经和脊髓损伤。当前 疼痛控制的主要药物包括镇痛剂和麻醉剂，这些治疗方法尽管有 不确定的疗效和已知的副作用。更安全、更有效的疼痛管理方法是 迫切需要，但基础研究中的知识差距阻碍了 新的治疗方法。为了加速这一过程，需要更好地理解细胞和分子基础。 疼痛信号是必需的。脊髓是传递疼痛相关信息的重要信号中枢。 外周器官和大脑之间的信号。作为中央感觉整合的第一个部位 神经系统(CNS)在中枢敏感化过程中起着至关重要的作用。很多注意力都集中在 参与这一过程的神经细胞类型和回路。然而，人们对此所知的要少得多 非神经细胞的贡献，如星形胶质细胞。而脊髓星形胶质细胞的形态变化 与慢性疼痛的发生和发展的关系已经有了很好的特征，对它们的了解很少 动态活动模式及其与神经元尖峰或性别特异性免疫反应的关系。 从历史上看，技术挑战阻碍了在临床前动物模型中进行这种测量 自然主义条件。双光子和小型化单光子成像的最新进展 Approach使实时测量表现良好的哺乳动物的细胞钙活动成为可能。这有 提供了关于皮肤中机械感受器和伤害性感受器的感觉信息如何敏锐地 激活背角神经元和星形胶质细胞。结合使用这些尖端成像方法 利用计算、遗传和行为技术，这项提议的目标是定义星形胶质细胞如何 钙活性变化与神经病理性疼痛发生和发展的关系及其靶向性操作 影响神经元和非神经元的反应，以及它如何改变分子信号和动物行为。 这项拟议研究的基本原理是，通过揭示细胞和分子机制 有助于疼痛的发生或进展，可以设计出新的止痛干预措施。三个具体目标将 1)确定在自然主义条件下，星形胶质细胞钙兴奋与神经病理性疼痛之间的关系 条件；2)确定抑制星形胶质细胞钙兴奋如何调节正常和异常感觉 处理，以及3)确定参与星形胶质细胞钙激发的分子通路 调节正常和异常的感觉加工。总而言之，这项工作将揭示 星形胶质细胞的活动在分子、细胞和行为水平上与神经病理性疼痛有关。它将延长 目前的模型表明，非神经细胞如何具体地参与持续性疼痛和中枢神经系统的广泛功能。