Nociceptor mechanisms in the transition from acute to chronic pain

从急性疼痛转变为慢性疼痛的伤害感受器机制

• 批准号: 8976453
• 负责人: JON DAVID LEVINE
• 金额: $ 9.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976453
• 关键词: Acute; Adenosine; Afferent Neurons; Agonist; Aplysia; Axon; Binding Proteins; CPE-binding protein; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Characteristics; Cyclic AMP; Development; Elements; Health; Heat-Shock Proteins 90; Hyperalgesia; Indium; Ion Channel; Maintenance; Mediating; Messenger RNA; Mitogen-Activated Protein Kinases; Modeling; Nerve Fibers; Neuronal Plasticity; Nociceptors; Pain; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phosphorylation; Polyadenylation; Pre-Clinical Model; Protein Kinase C; Proteins; Regulation; Role; Ryanodine Receptor Calcium Release Channel; Second Messenger Systems; Signal Pathway; Syndrome; Testing; Therapeutic Agents; Translations; autocrine; chronic pain; design; experience; inhibitor/antagonist; novel; novel strategies; receptor; research study; second messenger; versican

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.

描述（由适用提供）：从急性到慢性疼痛的过渡的概念，即认识到疼痛机制中可塑性的难以反向可塑性的概念，为开发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， 包括主要传入伤害感受器。我们建议检验以下假设：从急性疼痛到慢性疼痛的过渡模型中的神经塑性变化，涉及对病人外周末端的休眠mRNA的新蛋白质的翻译。重要的是，在初步研究中，我们发现翻译抑制剂能够逆转高过度过敏启动的神经塑性变化。 To investigate this mechanism, we will evaluate whether Cytoplasmic polyadenylation element binding protein (CPEB), a regulator of protein translation in axons that has been impregnated in neuroplasticity, orchestrates the effects of protein kinase C¿ (PKC¿) on a downstream protein, calcium-calmodulin kinase II (CaMKII), and the ryanodine receptor activation其中释放了Ca2+，可以激活CAMKII，这在高阈值Aplysia感觉神经元中已暗示。重要的是，所提出的实验将区分依赖性神经质的外周蛋白翻译，以及如何逆转。最后，我们还建议研究假说，即在camp依赖性的痛觉过敏的自分泌机制是PKC。在表达Primed伤害感受器的Hypergersia特征的延长时，也是PKC。以及确定第二个在PKC pkc sprempstreamspstrame的使者。这些研究的结果可以指导全新的治疗剂治疗慢性疼痛综合症的合理设计，以及介导延长剧院的PKC波的信号传导途径。