Chronification and resolution of nociceptive neural circuit sensitization

伤害性神经回路敏化的时间和分辨率

• 批准号: 10326845
• 负责人: Kathleen Erin McDonough
• 金额: $ 2.8万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2022-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326845
• 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 pain management; 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

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.

项目总结 慢性疼痛是一种严重的疾病，由各种不同的疾病产生和维持 机制，其中许多机制仍然知之甚少，这导致在提供有效的 治疗。慢性疼痛(如肿瘤性疼痛)的一个关键机制是中枢 脊髓水平上的可塑性变化有助于并维持高度伤害性感觉的敏化。 进一步增加复杂性的是，我们发现急性、过渡和慢性的不同机制 在我们的肿瘤性疼痛模型中，中枢敏化的阶段。为了更好地理解，因此 成功治疗慢性疼痛状况，这三个阶段的潜在机制，以及解决 慢性疼痛的原因，必须加以阐明。我已经证明了辣椒素敏感传入的兴奋 减弱sGABAn对低强度突触刺激的反应。此外，我已经证明了脊椎 小胶质细胞和炎症介导了中枢敏化的慢性期，这是一种肿瘤性疼痛状态的基础。 在拟议项目的F99阶段，我将进一步描述 中枢敏感化的急性期和维持期，重点放在1)伤害性感受器如何激活和随后 在急性期，活性氧物种的释放削弱了β纤维诱导的sGABA的激活，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期， 3)反应性小胶质细胞和炎性介质是否维持慢性期的损害。 在K00阶段，我将转到一个著名的疼痛研究实验室，通过以下方式研究其机制 在疼痛条件下，哪些促进分解的脂质介质，如分解素，调节失调，以及它们对 伤害性神经回路。此外，我还将研究分辨率和它们所影响的电路 被操纵以将慢性疼痛转化为解决疼痛。 总体而言，拟议项目将提供对编年表和解决方案的关键理解 伤害性神经回路敏化。这些最终将揭示新的治疗靶点，允许 开发更好的疼痛治疗方法。