In-vivo imaging of spinal and brain glial activation in low back pain patients

腰痛患者脊髓和脑胶质细胞激活的体内成像

• 批准号: 9237452
• 负责人: Marco Luciano Loggia
• 金额: $ 70.48万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237452
• 关键词: Acute; Affect; Animal Model; Animals; Anterior; Astrocytes; Back; Binding; Brain; Brain imaging; CD2 gene; Chronic; Chronic low back pain; Clinical; Data; Development; Disease; Evolution; Functional disorder; Generations; Healed; Human; Inflammatory; Intervention; Investigation; Knee; Laboratories; Laboratory Animals; Leg; Literature; Lobule; Longitudinal Studies; Low Back Pain; Magnetic Resonance Imaging; Maintenance; Medial; Microglia; Minocycline; Modeling; Motor Cortex; Natural History; Neuraxis; Neuroglia; Pain; Pain Disorder; Pain management; Pain-Free; Participant; Pathway interactions; Patients; Persistent pain; Pharmaceutical Preparations; Phase; Placebos; Play; Positron-Emission Tomography; Predisposing Factor; Preventive Intervention; Proteins; Role; Sacral spinal cord structure; Sampling; Scanning; Sciatica; Signal Transduction; Site; Somatosensory Cortex; Specificity; Spinal; Spinal Cord; Spine pain; Staging; Symptoms; Synapses; Testing; Thalamic structure; Time; Translations; Up-Regulation; Vertebral column; arm; base; chronic pain; cingulate cortex; clinically significant; cohort; cytokine; disability; experience; follow-up; glial activation; healing; healthy volunteer; human data; in vivo imaging; inhibitor/antagonist; model building; negative affect; novel; pain symptom; radioligand; somatosensory; spine bone structure

In animal models of pain, microglia and astrocytes become `activated' and start releasing pro- inflammatory cytokines and other products that further sensitize pain pathways. Thus, it is generally believed that glial cells actively contribute to the pathophysiology of persistent pain. Despite hundreds of studies with laboratory models, it is currently unclear whether glial cells have a role in human pain. Recently, however, our group has demonstrated that patients with chronic low back pain (cLBP) have increased brain levels of the 18kDa translocator protein (TSPO). In addition, preliminary data collected from a different cohort of cLBP patients suggest an increase in spinal cord TSPO levels as well. As TSPO upregulation is a marker of glial activation, these observations support a role for glial activation in human chronic pain. With the current proposal, which builds logically on our prior observations, we will compare spinal and brain glial activation in healthy volunteers, and patients with subacute (i.e., pain duration between 1 and 3 months) and chronic (i.e., pain duration > 1 year) low back pain. Scans will be performed with integrated Positron Emission Tomography / Magnetic Resonance (PET/MR) imaging and [11C]PBR28, a second- generation radioligand for TSPO, with an excellent ratio of specific-to-nonspecific binding. By comparing [11C]PBR28 scans in cLBP patients of different clinical presentation (i.e., with radicular pain vs axial pain) we will test the hypothesis that glial activation in the primary somatosensory/motor cortices follows a somatotopic organization that mirrors the somatic distribution of the patients' symptoms. Moreover, we will perform cross- sectional comparisons between subacute and chronic low back pain, as well as longitudinal studies of subacute low back pain patients across time, to capture the transition to chronic pain, or the return to pain-free status. These investigations will allow us to assess the temporal evolution of glial activation in humans with pain disorders. A subset of sLBP patients will be re-scanned after a 2-week treatment with either minocycline (which was recently found to reduce sLBP) or placebo. While minocycline is a known glial inhibitor in animal models, the mechanisms underlying its effect on human pain are unknown. Finally, we will compare the baseline status of glial activation in subacute patients that have subsequently transitioned to chronic pain, or have healed. This comparison will allow us to test the hypothesis that glial activation can predict transition from subacute to chronic pain. While this project is purposely focused on a specific condition (low back pain), the identification of a role of glia in the development and maintenance of persistent pain and pain-related disability will have important practical implications for the management of a wide range of pain disorders.

在疼痛的动物模型中，小胶质细胞和星形胶质细胞变为“活化”，并开始释放促进 炎性细胞因子和其他产品，以进一步敏感疼痛途径。因此，人们普遍认为 该神经胶质细胞积极促进持续性疼痛的病理生理学。尽管有数百种研究 实验室模型目前尚不清楚神经胶质细胞在人类疼痛中是否起作用。但是最近，我们的 小组表明，患有慢性腰痛（CLBP）的患者的大脑水平升高 18KDA转运蛋白（TSPO）。此外，从不同的CLBP组收集的初步数据 患者建议脊髓TSPO水平也增加。因为TSPO上调是神经胶质的标记 激活，这些观察结果支持人神经胶质激活在人类慢性疼痛中的作用。 随着当前的提议以我们先前的观察为逻辑建立，我们将比较脊柱和 健康志愿者和亚急性患者的脑胶质激活（即1至3的疼痛持续时间 几个月）和慢性（即疼痛持续时间> 1年）的腰痛。扫描将通过集成进行 正电子发射断层扫描 /磁共振（PET / MR）成像和[11C] PBR28，第二个 TSPO的生成放射性物体，具有特异性与非特异性结合的良好比例。通过比较 [11C] PBR28在不同临床表现的CLBP患者中扫描（即，有辐射疼痛与轴向疼痛） 将检验以下假设，即主体感/运动皮质中的神经胶质激活遵循体积 反映患者症状的躯体分布的组织。此外，我们将执行交叉 亚急性和慢性下背痛之间的分段比较，以及纵向研究 亚急性下腰痛患者跨时间，以捕获过渡到慢性疼痛或恢复无痛 地位。这些调查将使我们能够评估人类神经胶质激活的时间演变 疼痛障碍。两周治疗两种米诺环素后，将重新扫描SLBP患者的一部分 （最近发现可以减少SLBP）或安慰剂。而米诺环素是动物中已知的神经胶质抑制剂 模型，其对人类疼痛影响的机制尚不清楚。最后，我们将比较 随后转变为慢性疼痛或 已经治愈了。这种比较将使我们能够检验以下假设，即神经胶质激活可以预测从 亚急性到慢性疼痛。 虽然该项目故意专注于特定状况（腰痛），但识别角色 在持续性疼痛和与疼痛相关的残疾的发展和维持中神经胶质的 对多种疼痛障碍的管理的实际意义。