Translational Sciences, Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA.
Neuroimage. 2013 Jan 1;64:341-55. doi: 10.1016/j.neuroimage.2012.08.084. Epub 2012 Sep 7.
The earliest stages of osteoarthritis are characterized by peripheral pathology; however, during disease progression chronic pain emerges-a major symptom of osteoarthritis linked to neuroplasticity. Recent clinical imaging studies involving chronic pain patients, including osteoarthritis patients, have demonstrated that functional properties of the brain are altered, and these functional changes are correlated with subjective behavioral pain measures. Currently, preclinical osteoarthritis studies have not assessed if functional properties of supraspinal pain circuitry are altered, and if these functional properties can be modulated by pharmacological therapy either by direct or indirect action on brain systems. In the current study, functional connectivity was first assessed in order to characterize the functional neuroplasticity occurring in the rodent medial meniscus tear (MMT) model of osteoarthritis-a surgical model of osteoarthritis possessing peripheral joint trauma and a hypersensitive pain state. In addition to knee joint trauma at week 3 post-MMT surgery, we observed that supraspinal networks have increased functional connectivity relative to sham animals. Importantly, we observed that early and sustained treatment with a novel, peripherally acting broad-spectrum matrix metalloproteinase (MMP) inhibitor (MMPi) significantly attenuates knee joint trauma (cartilage degradation) as well as supraspinal functional connectivity increases in MMT animals. At week 5 post-MMT surgery, the acute pharmacodynamic effects of celecoxib (selective cyclooxygenase-2 inhibitor) on brain function were evaluated using pharmacological magnetic resonance imaging (phMRI) and functional connectivity analysis. Celecoxib was chosen as a comparator, given its clinical efficacy for alleviating pain in osteoarthritis patients and its peripheral and central pharmacological action. Relative to the vehicle condition, acute celecoxib treatment in MMT animals yielded decreased phMRI infusion responses and decreased functional connectivity, the latter observation being similar to what was detected following chronic MMPi treatment. These findings demonstrate that an assessment of brain function may provide an objective means by which to further evaluate the pathology of an osteoarthritis state as well as measure the pharmacodynamic effects of therapies with peripheral or peripheral and central pharmacological action.
骨关节炎的早期阶段以周围病理学为特征；然而，在疾病进展过程中，慢性疼痛会出现——这是骨关节炎的主要症状，与神经可塑性有关。最近涉及慢性疼痛患者（包括骨关节炎患者）的临床成像研究表明，大脑的功能特性发生了改变，这些功能变化与主观行为疼痛测量相关。目前，临床前骨关节炎研究尚未评估脊髓上疼痛回路的功能特性是否发生改变，以及这些功能特性是否可以通过药物治疗通过直接或间接作用于大脑系统来调节。在当前的研究中，首先评估了功能连接，以描述在啮齿动物内侧半月板撕裂（MMT）骨关节炎模型（一种具有外周关节创伤和敏感疼痛状态的骨关节炎手术模型）中发生的功能神经可塑性。除了 MMT 手术后第 3 周的膝关节创伤外，我们还观察到与假手术动物相比，脊髓上网络的功能连接增加。重要的是，我们观察到早期和持续使用新型外周作用广谱基质金属蛋白酶（MMP）抑制剂（MMPI）可显著减轻膝关节创伤（软骨降解）以及 MMT 动物中脊髓上功能连接的增加。在 MMT 手术后第 5 周，使用药物磁共振成像（phMRI）和功能连接分析评估了塞来昔布（选择性环氧化酶-2 抑制剂）对大脑功能的急性药效学作用。选择塞来昔布作为对照药物，因为它对缓解骨关节炎患者的疼痛具有临床疗效，并且具有外周和中枢药理学作用。与载体条件相比，MMT 动物中急性塞来昔布治疗导致 phMRI 输注反应降低和功能连接降低，后一观察结果与慢性 MMPi 治疗后检测到的结果相似。这些发现表明，大脑功能评估可能提供一种客观手段，进一步评估骨关节炎状态的病理学，并测量具有外周或外周和中枢药理学作用的治疗方法的药效学效应。
