Central sensitization in osteoarthritis pain: Validation of rodent models, development of biomarkers for diagnosis and anti-inflammatory inhibitors for treatment.

骨关节炎疼痛的中枢敏化：啮齿动物模型的验证、诊断用生物标志物的开发和治疗用抗炎抑制剂。

• 批准号: 441651-2013
• 负责人: Troncy, Eric
• 金额: $ 3.42万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Group
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=631014
• 关键词: Central; sensitization; osteoarthritis; pain; Validation

Osteoarthritis (OA) is the most common form of arthritis and a major cause of pain and disability in older adults. We hypothesized that innate immune system activation, best documented in response to pathogens, likely plays a role in the induction of inflammatory mediators and the specific cellular infiltrates seen in OA. We previously linked immune system activation to the processes of sensitization, thought to be the basis for arthritic pain that appears spontaneously (that is, at rest), and hyperalgesia (increased pain responses to noxious stimulation) and allodynia (pain in response to normally non-painful stimulation). We demonstrated this in both experimental rat and dog, as well as natural cat and dog, OA models. Sensitization also facilitates the efferent neuronal processes through which the nervous system influences the inflammatory/immune process. This could contribute to the frequently observed disparity between clinical pain severity and the extent of joint changes in subjects with OA. Such observations have prompted work to investigate the mechanisms of central pain perception in OA. By studying chronic pain syndromes in different species, we have validated a method of central sensitization assessment that includes specific neuroproteome quantification, neuromechanical testing, neurophysiological sensitization testing (mechanical temporal summation) and functional neuroimaging. We will apply these to the determination of the experimental rat OA model best suited to studying sensitization, before confirming the role of inflammatory/immune signalling pathways using genetically modified mouse models. Finally, to study the central role of pro-inflammatory cytokines in OA structure and pain pathogenesis, we will block interleukin-1 receptor binding using various pharmacological approaches. Our hypothesis is that the inhibition produced by an original negative allosteric modulator will have the greatest effects on joint alterations and neuronal sensitization, along with the fewest side effects. This will open the field for an innovative anti-inflammatory pharmacological approach to early OA.

骨关节炎（OA）是最常见的关节炎形式，也是老年人疼痛和残疾的主要原因。我们假设先天免疫系统激活，在对病原体的反应中有最好的记录，可能在炎症介质的诱导和OA中所见的特异性细胞浸润中起作用。我们之前将免疫系统激活与致敏过程联系起来，认为这是自发出现的关节炎疼痛（即在休息时）、痛觉过敏（对有害刺激的疼痛反应增加）和异常性疼痛（对正常无痛感刺激的疼痛反应）的基础。我们在实验大鼠和狗，以及猫和狗的OA模型中都证明了这一点。致敏还促进神经系统影响炎症/免疫过程的传出神经元过程。这可能导致OA患者临床疼痛严重程度和关节变化程度之间经常观察到的差异。这些观察结果促使研究OA中枢性疼痛感知的机制。通过对不同物种慢性疼痛综合征的研究，我们验证了一种中枢致敏评估方法，该方法包括特异性神经蛋白质组量化、神经力学测试、神经生理致敏测试（机械时间累积）和功能神经影像学。在使用转基因小鼠模型确认炎症/免疫信号通路的作用之前，我们将把这些应用于确定最适合研究致敏性的实验性大鼠OA模型。最后，为了研究促炎细胞因子在OA结构和疼痛发病机制中的核心作用，我们将使用各种药理学方法阻断白细胞介素-1受体的结合。我们的假设是，由原始负变构调节剂产生的抑制将对关节改变和神经元敏化产生最大的影响，同时副作用最小。这将为早期OA的创新抗炎药理学方法开辟领域。