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

项目摘要 多年来，抗抑郁药一直是慢性疼痛的一线治疗药物。然而，临床疗效 选择性5-羟色胺再摄取抑制剂（SSRI）在不同的药物中是中度和高度可变的。 条件，这需要更深入地了解5-HT在调节疼痛中的作用， 受体特异性方式。最近人们感兴趣的一个区域是杏仁核。神经病理性损伤后， 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。 抑制杏仁核基底外侧核（BLA）中的5-HT 2C受体“允许”SSRI诱导的 减轻啮齿动物的疼痛。此外，5-HT 2C的遗传破坏可防止神经性疼痛的发展。 总之，这些数据支持通过5-HT 2C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是用来治疗疼痛的 为了验证这一假设，有必要监测BLA中5-HT动态和神经活动随时间的变化 从急性期到慢性期的神经病理性损伤后。目前，没有可植入传感器能够进行多- 通道检测时相和紧张性5-HT释放，同时记录几天内的电生理学。在这 提出了一种新型的柔性多电极阵列GC-MEAs 微电极位点和柔性和可固化聚合物基板上的互连。GC-MEA将能够 相位5-HT（快速扫描循环伏安法）和强直5-HT（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代表了一个实质性的技术 对5-HT动力学理解的突破。首先（目标1），我们将优化制造工艺， 材料，以获得最强大的设备，具有稳定，灵敏和选择性的检测。下一步（目标2）我们将 在BLA中对这项技术进行为期四周的急性和慢性验证。最后（目标3），我们将监测主音 急性期和慢性期小鼠BLA中5-HT和神经活动的变化 神经损伤（SNI），有或没有SSRI治疗和5-HT 2C抑制BLA。

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.