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: 8827433
• 负责人: JON DAVID LEVINE
• 金额: $ 60.39万
• 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/8827433
• 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（由申请人提供）：从急性疼痛向慢性疼痛过渡的概念认识到逆转疼痛机制可塑性的困难，为临床前模型的开发提供了动力，以评估疼痛回路元件中的神经可塑性， 包括初级传入伤害感受器。我们建议测试的假设，神经可塑性的变化，从急性到慢性疼痛，痛觉过敏引发的过渡模型，涉及翻译新的蛋白质从休眠mRNA在外周终端的伤害感受器。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。为了研究这一机制，我们将评估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）的作用，CPEB是轴突中蛋白质翻译的调节因子，与神经可塑性有关。）作用于下游蛋白质，钙-钙调蛋白激酶II（CaMKII），并且其ryanodine受体激活释放可激活CaMKII的Ca 2+，其与高阈值失智症感觉神经元的神经可塑性有关。重要的是，拟议的实验将区分外周蛋白翻译依赖性神经可塑性变化，以及它如何被逆转。最后，我们还建议调查的假设，cAMP依赖性的自分泌机制的痛觉过敏是上游的PKC <$在表达的延长痛觉过敏的特点，启动伤害感受器，并确定第二信使是下游的PKC <$。这些研究的结果可以指导用于治疗慢性疼痛综合征的全新类型的治疗剂的合理设计，以及介导延长的痛觉过敏的PKC？下游的信号通路。