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

基本信息

批准号：
10419830
负责人：
Elisa Castagnola
金额：
$ 36.24万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2022-09-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10419830
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 Electrodes Electrophysiology (science)Failure Film Fluvoxamine Genetic Histologic Hybrids Hydrogen Peroxide Implant Infusion procedures Injury Learning Link Maintenance Measurement Measures Mechanics Memory Metals Microdialysis Microelectrodes Modeling Monitor Moods Morphology Mus Natural graphite Nervous system structure 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 Thinness Time Tissues Trace metal chronic pain chronic pain management clinical efficacy design detection sensitivity experimental study extracellular flexibility implantation implanted sensor improved in vivo inhibitor therapy interest mouse model multi-electrode arrays nerve injury novel pain reduction painful neuropathy prevent receptor relating to nervous system response sensor spared nerve tool

项目摘要

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，但其临床疗效却不尽如人意。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。最近感兴趣的一个领域是神经病理性损伤后的神经活动。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从急性到慢性阶段的神经性损伤后，目前没有植入式传感器能够进行多种处理。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。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” GC-MEA 将能够在柔性超薄聚合物基底上进行微电极位点和互连。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 代表了一项实质性技术。首先（目标 1），我们将优化制造工艺和对 5-HT 动力学的理解。材料以获得具有稳定、灵敏和选择性检测的最坚固的设备。下一步（目标 2）我们将。在 BLA 中急性和长期验证这项技术四个星期最后（目标 3），我们将监测补品。和阶段性 5-HT 以及小鼠 BLA 在 Spared 急性期和慢性期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。