In vivo mechanical loading and tissue adaptation in vertebrae: Inflammation, pain and opioid effects

为了对腰椎形态、一侧的机械负荷和运动以及另一侧的炎症和疼痛的相互作用进行机制分析，我们将使用小鼠体内模型。我们将采用一种既定的椎体加载方案，允许轴向压缩暴露在不同形状的脊柱，识别局部组织和炎症反应，并首次通过阿片受体激活来调节疼痛。使用纵向体内成像（微CT）和组织形态计量学分析，我们将研究脊柱负荷（2周，5天/周）如何影响脊髓节段（皮质、小梁和椎间盘结构）的组织形态，以及它是否影响这些和相应组织（脊髓、背根神经节）中的炎症介质（质子、自由基）和神经肽（阿片、P物质），以及由此产生的骨髓局部免疫室。通过执行Roussouly等人定义的基本形状（I-IV），我们的目标是确定形状如何影响压迫下的组织适应，以及在释放受约束的形状和疼痛调节后，这种适应可以在多大程度上被“拯救”。通过这种方法，我们的目标是实现对肌肉骨骼脊柱组织如何适应机械负荷以及如何调节这种负荷引起的疼痛的机制理解。我们假设机械负荷诱导组织和免疫室调节，可通过局部激活阿片受体补偿。

To allow for mechanistic analyses of the interplay of lumbar spine morphology, mechanical loading and movement on the one side and resulting inflammation and pain on the other, we will use an in vivo mouse model. We will employ an established vertebral loading protocol that allows axial compression of the spine exposed to different shapes, identify the local tissue and inflammatory reaction and – for the first time – modulate pain by opioid receptor activation. Using longitudinal in vivo imaging (µCT) and histomorphometric analysis, we will investigate how spine loading (for 2 weeks, 5 days/week) impacts tissue morphology across spinal segments (cortical, trabecular and disc structures) and whether it influences inflammatory mediators (protons, radicals) and neuropeptides (opioids, substance P) in these and corresponding tissues (spinal cord, dorsal root ganglia) as well as the resulting local immune compartments in the bone marrow. By enforcing the elementary shapes (I-IV) defined by Roussouly et al., we aim to determine how shapes influence tissue adaptation under compression and to what degree such adaptation could be “rescued” after releasing the constrained shapes and by pain modulation. With this approach, we aim to achieve a mechanistic understanding of how musculoskeletal spine tissues adapt to mechanical loading and how this load-induced pain can be modulated. We hypothesize that mechanical loading induces tissue and immune compartment modulations that can be compensated by a local activation of opioid receptors.