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

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。我们推测，先天免疫系统的激活，最好地记录了对病原体的反应，可能在炎性介质的诱导和在OA中看到的特定的细胞渗透中发挥作用。我们以前将免疫系统的激活与敏化过程联系在一起，敏化被认为是自发出现的关节炎疼痛(即休息时)、痛觉过敏(对伤害性刺激的疼痛反应增加)和超敏(对正常非疼痛刺激的疼痛反应)的基础。我们在实验大鼠和狗以及自然猫和狗的OA模型中都证明了这一点。敏感化还促进传出神经过程，神经系统通过这些过程影响炎症/免疫过程。这可能导致经常观察到的骨性关节炎受试者的临床疼痛严重程度和关节改变程度之间的差异。这些观察结果促使人们研究骨性关节炎中枢性痛觉的机制。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敏化评估方法，该方法包括特异性神经蛋白质组定量、神经机械测试、神经生理学敏化测试(机械性时间总和)和功能神经成像。我们将把这些应用于最适合研究致敏作用的实验性大鼠骨性关节炎模型的确定，然后使用转基因小鼠模型确认炎症/免疫信号通路的作用。最后，为了研究促炎细胞因子在骨性关节炎结构和疼痛发病机制中的中心作用，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，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，同时副作用最少。这将为早期骨性关节炎提供一种创新的抗炎药理方法。

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.