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... 炎性细胞因子和其他进一步敏化疼痛通路的产品。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积极作用。尽管有数百项关于 在实验室模型中，目前尚不清楚神经胶质细胞是否在人类疼痛中起作用。然而最近，我们的 研究小组证实，慢性下腰痛(CLBP)患者的大脑中 18 kDa转位蛋白(TSPO)。此外，从不同的cLBP队列收集的初步数据 患者建议脊髓TSPO水平也会增加。由于TSPO上调是神经胶质细胞的标志 激活，这些观察支持胶质细胞激活在人类慢性疼痛中的作用。 目前的建议建立在我们之前观察到的逻辑基础上，我们将比较脊柱和 健康志愿者和亚急性(即疼痛持续时间在1到3之间)患者的脑胶质细胞激活 慢性(即疼痛持续时间&1年)腰背痛。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[11C]PBR28，第二个- 产生TSPO的放射性配基，具有良好的特异性与非特异性结合比率。通过比较 [11C]对不同临床表现(即神经根性疼痛与轴性疼痛)的cLBP患者进行PBR28扫描 将检验以下假设：躯体感觉/运动皮质中的神经胶质细胞在躯体刺激后被激活 反映患者症状的躯体分布的组织。此外，我们还将执行交叉- 亚急性和慢性下腰痛的横断面比较以及对 亚急性腰背痛患者跨越时间，捕捉到慢性疼痛的过渡，或恢复无痛 状态。这些研究将使我们能够评估人类神经胶质细胞激活的时间演变 疼痛障碍。一组SLBP患者将在接受米诺环素或米诺环素治疗两周后重新扫描 (最近发现可以降低SLBP)或安慰剂。而米诺环素是一种已知的动物神经胶质抑制物 在模型中，其对人类疼痛的潜在作用机制尚不清楚。最后，我们将比较 随后转变为慢性疼痛的亚急性患者的神经胶质激活基线状态，或 已经痊愈了。这种比较将使我们能够检验这样的假设，即胶质细胞的激活可以预测 亚急性到慢性疼痛。 虽然这个项目是有目的地关注一种特定的情况(下腰痛)，但确定一个角色 神经胶质细胞在持续性疼痛的发生和维持以及疼痛相关的残疾中将具有重要的意义 对于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.