Probing the role of serotonin in neuropathic pain with flexible carbon microelectrode arrays

用柔性碳微电极阵列探讨血清素在神经性疼痛中的作用

• 批准号: 10734710
• 负责人: Elisa Castagnola
• 金额: $ 28.78万
• 依托单位: LOUISIANA TECH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734710
• 关键词: Acids; Acute; Adhesions; Affect; Amygdaloid structure; Analgesics; Anatomy; Antidepressive Agents; Area; Biological; Carbon; Carbon Nanotubes; Cell Nucleus; Cells; Chronic; Chronic Phase; Cognition; Data; Detection; Development; Devices; Electric Stimulation; Electrodes; Electrophysiology (science); Failure; Film; Fluvoxamine; Genetic; Glass; Histologic; Hybrids; Hydrogen Peroxide; Implant; Infusion procedures; Injury; Learning; Link; Maintenance; Measurement; Measures; Mechanics; Memory; Metals; Microdialysis; Microelectrodes; Modeling; Monitor; Moods; Morphology; Mus; Nervous System; Neuropathy; Pain; Pattern; Performance; Periodicity; Pharmaceutical Preparations; Phase; Polymers; Process; Property; Protocols documentation; Rewards; Rodent; Role; Running; Saline; Scanning; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Receptor 5-HT2C; Signal Transduction; Site; Surface; Technology; Testing; Therapeutic; Thinness; Time; Tissues; Trace metal; chronic pain; chronic pain management; clinical efficacy; design; detection sensitivity; experimental study; extracellular; fabrication; flexibility; implantation; implanted sensor; improved; in vivo; interest; mouse model; multi-electrode arrays; nerve injury; neural; novel; pain reduction; painful neuropathy; prevent; receptor; response; sensor; spared nerve; technology platform; technology validation; tool

PROJECT SUMMARY Antidepressants have been front-line treatments for chronic pain for years. However, clinical efficacy of selective serotonin reuptake inhibitors (SSRI’s) has been moderate and highly variable across different conditions, which calls for a deeper understanding of 5-HT’s role in modulating pain, in an anatomical and receptor-specific manner. One area of recent interest is the amygdala. After neuropathic injury, neural activity in the amygdala changes during the chronification process, while changes in 5-HT have also been detected. Inhibition of the 5-HT2C receptor in the basolateral nucleus of the amygdala (BLA) “permits” SSRI-induced reduction of pain in rodents. In addition, genetic disruption of 5-HT2C prevents neuropathic pain development. Taken together these data support the hypothesis that increases in 5-HT signaling through the 5-HT2C contribute to the development and maintenance of chronic pain and ultimately influence the ability of SSRI’s to be used to treat pain. To test this hypothesis, it is necessary to monitor 5-HT dynamics and neural activity over time in the BLA after neuropathic injury from acute through chronic phases. Currently no implantable sensor is capable of multi- channel detection of both phasic and tonic 5-HT release while recording electrophysiology over days. In this proposal, we introduce novel flexible multi-electrode arrays “GC-MEAs” that made of glassy carbon microelectrode sites and interconnects on flexible and ultrathin polymer substrate. The GC-MEAs will be capable of phasic 5-HT (with fast scan cyclic voltammetry) and tonic 5-HT (with square wave voltammetry) detections, as well as neural activity recordings in vivo over 4 weeks. Our GC-MEAs represent a substantive technological breakthrough in the understanding of 5-HT dynamics. First (Aim 1), we will optimize the fabrication process and materials to obtain the most robust device with stable, sensitive and selective detection. Next (Aim 2) we will validate this technology in the BLA acutely and chronically for four weeks. Finally (Aim 3), we will monitor tonic and phasic 5-HT as well as neural activities in the BLA of mice during acute and chronic phases of a Spared Nerve Injury (SNI), with or without SSRI treatment and 5-HT2C inhibition in BLA.

项目概要 多年来，抗抑郁药一直是慢性疼痛的一线治疗方法。然而，临床疗效 选择性血清素再摄取抑制剂（SSRI）在不同的人群中具有中等和高度可变性。 需要更深入地了解 5-HT 在调节疼痛、解剖学和疼痛方面的作用。 受体特异性方式。最近感兴趣的领域之一是杏仁核。神经性损伤后，神经活动 杏仁核在慢性化过程中发生变化，同时也检测到 5-HT 的变化。 杏仁核基底外侧核 (BLA) 中 5-HT2C 受体的抑制“允许”SSRI 诱导 减少啮齿类动物的疼痛。此外，5-HT2C 的基因破坏可防止神经性疼痛的发生。 综合起来，这些数据支持通过 5-HT2C 增加 5-HT 信号传导的假设 有助于慢性疼痛的发展和维持，并最终影响 SSRI 用于治疗疼痛。 为了检验这一假设，有必要监测 BLA 中 5-HT 动态和神经活动随时间的变化 神经性损伤后从急性到慢性阶段。目前还没有植入式传感器能够实现多种功能 通道检测阶段性和强直性 5-HT 释放，同时记录数天的电生理学。在这个 提案中，我们引入了由玻碳制成的新型柔性多电极阵列“GC-MEA” 柔性超薄聚合物基板上的微电极位置和互连。 GC-MEA 将能够 相 5-HT（使用快速扫描循环伏安法）和强效 5-HT（使用方波伏安法）检测， 以及 4 周内的体内神经活动记录。我们的 GC-MEA 代表了实质性技术 对 5-HT 动力学的理解取得了突破。首先（目标 1），我们将优化制造工艺并 材料以获得具有稳定、灵敏和选择性检测的最坚固的设备。接下来（目标 2）我们将 在 BLA 中对这项技术进行为期四个星期的急性和长期验证。最后（目标 3），我们将监控补品 和阶段性 5-HT 以及小鼠在 Spared 急性期和慢性期 BLA 中的神经活动 神经损伤 (SNI)，有或没有 SSRI 治疗和 BLA 中的 5-HT2C 抑制。