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

在疼痛的动物模型中，小胶质细胞和星形胶质细胞被“激活”，并开始释放前- 炎性细胞因子和其它进一步使疼痛途径敏感的产物。因此，人们普遍认为， 神经胶质细胞在持续性疼痛的病理生理学中起着积极的作用。尽管有数百项研究， 虽然神经胶质细胞在实验室模型中的作用已经得到证实，但目前还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 研究小组已经证明，慢性下腰痛（cLBP）患者的大脑中 18 kDa转运蛋白（TSPO）。此外，从不同cLBP队列收集的初步数据 患者也提示脊髓TSPO水平增加。由于TSPO上调是神经胶质细胞增殖的标志物， 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。 根据目前的建议，这在逻辑上建立在我们以前的观察，我们将比较脊柱和 健康志愿者，和亚急性（即，疼痛持续时间介于1和3之间 月）和慢性（即，疼痛持续时间> 1年）腰痛。扫描将使用集成的 正电子发射断层扫描/磁共振（PET/MR）成像和[11 C] PBR 28，第二个- 产生TSPO的放射性配体，具有优异的特异性与非特异性结合比率。通过比较 [11 C] PBR 28扫描在不同临床表现的cLBP患者中（即，神经根痛vs轴性痛）， 将测试这一假设，即在初级躯体感觉/运动皮层神经胶质细胞激活遵循躯体位置 反映患者症状的躯体分布的组织。此外，我们将执行交叉- 亚急性和慢性下腰痛之间的横断面比较，以及 亚急性下腰痛患者跨越时间，捕捉向慢性疼痛的过渡，或恢复到无痛 status.这些研究将使我们能够评估人类神经胶质激活的时间演变， 疼痛障碍一部分sLBP患者将在接受米诺环素治疗2周后重新扫描， （最近发现可降低sLBP）或安慰剂。二甲胺四环素是一种已知的神经胶质抑制剂， 尽管在模型中，其对人类疼痛的作用机制尚不清楚。最后，我们将比较 随后转变为慢性疼痛的亚急性患者中神经胶质活化的基线状态，或 已经痊愈了这种比较将使我们能够测试假设，即胶质细胞激活可以预测从 亚急性至慢性疼痛。 虽然这个项目是故意集中在一个特定的条件（腰痛），确定一个角色， 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。 对广泛的疼痛障碍的管理的实际意义。

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.