Nociceptor mechanisms in the transition from acute to chronic pain

描述(申请人提供)：从急性疼痛到慢性疼痛的转变的概念认识到扭转疼痛机制的可塑性是困难的，这为临床前模型的发展提供了动力，以评估疼痛回路元素的神经可塑性， 包括初级传入伤害性感受器。我们提出的假设是，在一个从急性到慢性疼痛过渡的模型中，神经可塑性的变化，即痛觉过敏性启动，涉及到伤害性感受器外周末端休眠mRNA中的新蛋白的翻译。重要的是，在初步研究中，我们发现翻译抑制剂能够逆转痛觉过敏引发的神经可塑性变化。为了探讨这一机制，我们将评估与神经可塑性有关的轴突蛋白翻译调节因子-细胞质多聚腺苷酸化元件结合蛋白(CPEB)是否协调蛋白激酶C(PKC)对下游蛋白钙钙调素激酶II(CaMKII)的影响，以及Ryanodine受体的激活，该受体释放可激活CaMKII的钙离子，这与高阈值海兔感觉神经元的神经可塑性有关。重要的是，拟议的实验将区分依赖外周蛋白翻译的神经可塑性变化，以及它可能被逆转的方式。最后，我们还提出了一种假设，即cAMP依赖的痛觉过敏自分泌机制是在PKC的上游，在启动的伤害性感受器的痛敏特征的延长的表达中，我们还提出了这一假设，并确定了PKC的下游的第二信使。这些研究结果可以指导合理设计用于治疗慢性疼痛综合征的全新的治疗药物，以及介导长时间痛觉过敏的PKC下游信号通路。

DESCRIPTION (provided by applicant): The concept of a transition from acute to chronic pain that recognizes the difficulty to reverse plasticity in pain mechanisms, has provided the impetus for the development of preclinical models to evaluate neuroplasticity in elements of pain circuits, including in the primary afferent nociceptor. We propose to test the hypothesis that neuroplastic changes in a model of the transition from acute to chronic pain, hyperalgesic priming, involves translation of new protein from dormant mRNA in the peripheral terminal of the nociceptor. Importantly, in preliminary studies we have found that translation inhibitors are able to reverse the neuroplastic changes underlying hyperalgesic priming. To investigate this mechanism, we will evaluate whether cytoplasmic polyadenylation element binding protein (CPEB), a regulator of protein translation in axons that has been implicated in neuroplasticity, orchestrates the effects of protein kinase C¿ (PKC¿) on a downstream protein, calcium-calmodulin kinase II (CaMKII), and the ryanodine receptor activation of which releases Ca2+ which can activate CaMKII, which has been implicated in neuroplasticity in high threshold Aplysia sensory neurons. Importantly the proposed experiments will distinguish between the peripheral protein translation dependent neuroplastic changes, and how it might be reversed. Finally, we also propose to investigate the hypothesis that a cAMP-dependent autocrine mechanism of hyperalgesia is upstream of PKC¿ in the expression of the prolongation of hyperalgesia characteristic of the primed nociceptor, and also identify the second messengers that are downstream of PKC¿. The results of these studies could guide the rational design of entirely new classes of therapeutic agents for the treatment of chronic pain syndromes, and the signaling pathways downstream of PKC¿ that mediate the prolonged hyperalgesia.