Chronification and resolution of nociceptive neural circuit sensitization

伤害性神经回路敏化的时间和分辨率

基本信息

批准号：
10157720
负责人：
Kathleen Erin McDonough
金额：
$ 3.58万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-15 至 2022-12-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10157720
关键词：
Acute Adult Affect Amyloid beta-Protein Animal Model Area Attenuated Back Brain-Derived Neurotrophic Factor Capsaicin Chronic Chronic Phase Data Development Electrophysiology (science)Family Female Fiber Goals Impairment Inflammation Inflammation Mediators Injury Interneurons Knowledge Laboratory Research Lipids Maintenance Mass Spectrum Analysis Mediating Microglia Modeling Molecular Neuroglia Nociception Nociceptors Pain Pain Research Pain management Pathway interactions Peripheral Phase Phase Transition Play Population Prevention Reactive Oxygen Species Refractory Research Research Project Grants Resolution Role Signal Pathway Site Spinal Spinal Cord Spinal cord posterior horn Synapses Syndrome Techniques United States Work central sensitization chronic back pain chronic pain chronic painful condition control theory effective therapy healing injured insight interest lipid mediator male mouse model neural circuit neuronal circuitry new therapeutic target novel pain chronification pain model painful neuropathy response sensory input sexual dimorphism skills

项目摘要

PROJECT SUMMARY Chronic pain is a serious condition which is produced and maintained by a variety of different mechanisms, many of which remain poorly understood This has led to difficulties in providing effective treatments. One key mechanism underlying chronic pain conditions, such as nociplastic pain, is central sensitization in which plastic changes at the level of the spinal cord contribute to and maintain hypernociception. To add further complexity, we have found that different mechanisms underlie the acute, transition, and chronic phases of central sensitization in our model of nociplastic pain. In order to better understand, and therefore successfully treat, chronic pain conditions, the mechanisms underlying these three phases, as well as resolution of chronic pain, must be elucidated. Already, I have shown that excitation of capsaicin-sensitive afferents attenuates the response of sGABAn to low-intensity synaptic stimulation. Furthermore, I have shown that spinal microglia and inflammation mediate the chronic phase of central sensitization underlying a nociplastic pain state. In the F99 phase of the proposed project, I will further characterize the neuronal circuitry underlying the acute and maintenance phases of central sensitization, focusing on 1) how nociceptor activation and subsequent release of reactive oxygen species impair Aβ-fiber-evoked sGABAn activation in the acute phase, 2) whether such impairment allows low-threshold afferent inputs to activate spinal microglia to drive the transition phase, and 3) if reactive microglia and inflammatory mediators maintain the impairment in the chronic phase. In the K00 phase, I will move to a prominent pain research laboratory to investigate the mechanisms by which pro-resolution lipid mediators, such as resolvins, are dysregulated in pain conditions, and their effect on nociceptive circuitry. Additionally, I will investigate how resolvins and the circuitry which they effect may be manipulated to convert chronic pain back to resolving pain. Overall, the proposed project will provide key understanding of the chronification and resolution of nociceptive neural circuit sensitization. These will ultimately reveal new therapeutic targets, allowing for the development of better pain treatments.

项目概要慢性疼痛是一种严重的疾病，由多种不同的原因产生和维持。机制，其中许多仍然知之甚少，这导致难以提供有效的机制慢性疼痛（例如伤害性疼痛）的一种关键机制是核心机制。致敏作用，其中脊髓水平的塑性变化有助于并维持过度伤害感受。为了进一步增加复杂性，我们发现急性、过渡和慢性疾病背后存在不同的机制。为了更好地理解我们的伤害性疼痛模型中的中枢敏化阶段。成功治疗慢性疼痛状况、这三个阶段的机制以及解决方案我已经证明了辣椒素敏感传入神经的兴奋。减弱 sGABAn 对低强度突触刺激的反应此外，我已经证明脊髓。小胶质细胞和炎症介导伤害性疼痛状态下的中枢敏化的慢性阶段。在拟议项目的 F99 阶段，我将进一步表征底层的神经电路中枢敏化的急性期和维持期，重点关注 1) 伤害感受器如何激活以及随后的反应活性氧的释放会损害急性期 Aβ 纤维诱发的 sGABAn 激活，2) 是否这种损伤允许低阈值传入输入激活脊髓小胶质细胞以驱动过渡阶段， 3）反应性小胶质细胞和炎症介质是否在慢性期维持损伤。在K00阶段，我将前往一家著名的疼痛研究实验室，通过以下方式研究其机制：哪些促消退脂质介质（例如消退素）在疼痛条件下失调，及其对疼痛的影响此外，我将研究如何解决伤害性电路及其影响的电路。操纵将慢性疼痛转回缓解疼痛。总体而言，拟议的项目将提供对时间安排和解决方案的关键理解这些将最终揭示新的治疗靶点，从而允许开发更好的疼痛治疗方法。