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: 9513066
• 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/9513066
• 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; Human; Inflammatory; 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; Pharmacology; 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; 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; negative affect; novel; pain model; pain patient; pain reduction; pain symptom; predictive modeling; radioligand; somatosensory; spine bone structure; treatment arm

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被“激活”并开始释放亲 炎症细胞因子和其他进一步使疼痛通路变得敏感的产物。因此，人们普遍认为 神经胶质细胞积极促进持续性疼痛的病理生理学。尽管有数百项研究 实验室模型中，目前尚不清楚神经胶质细胞是否在人类疼痛中发挥作用。然而最近，我们的 研究小组已经证明，慢性腰痛（cLBP）患者的大脑中 18kDa 易位蛋白 (TSPO)。此外，从不同的 cLBP 队列中收集的初步数据 患者的脊髓 TSPO 水平也有所增加。由于 TSPO 上调是胶质细胞的标志 激活，这些观察结果支持神经胶质激活在人类慢性疼痛中的作用。 目前的提议在逻辑上建立在我们之前的观察基础上，我们将比较脊柱和 健康志愿者和亚急性患者（即疼痛持续时间在 1 至 3 秒之间）的脑胶质细胞激活 月）和慢性（即疼痛持续时间 > 1 年）腰痛。扫描将通过集成的 正电子发射断层扫描/磁共振 (PET/MR) 成像和 [11C]PBR28 TSPO 的新一代放射性配体，具有极佳的特异性与非特异性结合比率。通过比较 [11C]PBR28 扫描不同临床表现的 cLBP 患者（即，根性疼痛与轴性疼痛） 将检验以下假设：初级体感/运动皮质中的神经胶质激活遵循体位 反映患者症状的躯体分布的组织。此外，我们还将进行跨 亚急性和慢性腰痛之间的截面比较，以及纵向研究 亚急性腰痛患者随时间变化，捕捉向慢性疼痛的过渡，或恢复无痛状态 地位。这些研究将使我们能够评估人类神经胶质激活的时间演化 疼痛障碍。一部分 sLBP 患者在使用米诺环素治疗 2 周后将接受重新扫描 （最近发现可以降低 sLBP）或安慰剂。虽然米诺环素是动物体内​​已知的神经胶质抑制剂 模型中，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的亚急性患者神经胶质激活的基线状态，或 已经痊愈了。这种比较将使我们能够检验神经胶质激活可以预测从 亚急性至慢性疼痛。 虽然该项目有意关注特定病症（腰痛），但角色的识别 神经胶质细胞在持续性疼痛和疼痛相关残疾的发展和维持中的作用将具有重要意义 对治疗多种疼痛疾病的实际意义。