A new animal model for stress-induced transition from acute to chronic pain

压力引起的急性疼痛向慢性疼痛转变的新动物模型

• 批准号: 9090015
• 负责人: Feng Tao
• 金额: $ 11.27万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-13 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9090015
• 关键词: AMPA Receptors; Acids; Acute; Address; Animal Model; Animals; Chronic; Complex; Development; Environmental Risk Factor; Event; Feedback; Goals; Health; Hormones; Human; Laboratories; Light; Long-Term Potentiation; Mediating; Membrane; Modeling; Molecular; Mutant Strains Mice; Mutation; N-Methyl-D-Aspartate Receptors; Nociception; Operative Surgical Procedures; Pain; Pathogenesis; Patients; Phosphorylation; Phosphorylation Site; Play; Posterior Horn Cells; Postoperative Pain; Postoperative Period; Probability; Process; Protein Kinase; Psychological Stress; Regulation; Reporting; Role; Spinal; Spinal Cord; Stress; Surface; Surgical incisions; Swimming; Synapses; central sensitization; chronic pain; experience; operation; pain behavior; pre-clinical; psychosocial; response; trafficking

DESCRIPTION (provided by applicant): The transition from acute to chronic pain is likely to result from a complex combination of mechanisms. It is important to develop a useful preclinical animal model that can replicate the complexity of the human condition. Previous studies have shown that psychosocial and socio-environmental factors are involved in the development of chronic postsurgical pain. In our preliminary studies, we found that forced swim stress significantly enhances plantar incision-induced �-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation and greatly prolongs plantar incision-induced pain, but forced swim stress alone does not produce pain behaviors; we also found that targeted mutation of AMPA receptor GluA1 phosphorylation site Ser831 significantly inhibits stress-induced prolongation of incisional pain. Thus, stress may induce pain transition by regulating AMPA receptor phosphorylation. Recently, we further found that forced swim stress significantly increases GluA1 membrane surface expression and GluA2 internalization and thereby enhances synaptic AMPA receptor switch from Ca2+-impermeable (GluA2-containing) to Ca2+-permeable (GluA2-lacking) in the spinal dorsal horn neurons. This switch will increase Ca2+ influx and further activate Ca2+-dependent protein kinases, thereby promoting AMPA receptor phosphorylation and other phosphorylation-triggered activities. This positive feedback loop may contribute to the molecular mechanisms that underlie stress- induced pain transition. Therefore, we hypothesize that regulation of AMPA receptor phosphorylation and phosphorylation-triggered synaptic AMPA receptor switch from Ca2+-impermeable to Ca2+-permeable contribute to a key mechanism by which stress induces the transition from acute to chronic pain. To address this central hypothesis, we will combine plantar incision with different levels of stress to develop a new animal model to study pain transition (specific aim 1), we will investigate stress-produced regulation of AMPA receptor activities (phosphorylation, trafficking, synaptic targeting, and subunit composition change) in our pain transition model (specific aim 2), and we will investigate the role of phosphorylation-triggered switch of AMPA receptors from Ca2+-impermeable to Ca2+-permeable in stress-induced pain transition (specific aim 3). The overall goal of this proposal is to develop a new animal model for pain transition study and provide critical evidence to characterize the pain transition model. The proposed studies will demonstrate the role of stress- produced AMPA receptor regulation in the transition from acute to chronic pain and shed new light on the pathogenesis of chronic postsurgical pain.

描述(由申请人提供)：从急性疼痛到慢性疼痛的转变可能是一种复杂的机制组合的结果。重要的是开发一种有用的临床前动物模型，能够复制人类状况的复杂性。先前的研究表明，心理社会和社会环境因素参与了慢性手术后疼痛的发展。在我们的初步研究中，我们发现强迫游泳应激显著增强了足底切开诱导的�-amino-3-hydroxy-5-methyl-4-isoxazolepropionic酸(AMPA)受体的磷酸化，并显著延长了足底切开诱导的疼痛，但强迫游泳应激本身并不产生疼痛行为；我们还发现AMPA受体GluA1磷酸化位点Ser831的靶向性突变显著抑制了应激诱导的切开疼痛的延长。因此，应激可能通过调节AMPA受体的磷酸化来诱导痛觉转换。最近，我们进一步发现，强迫游泳应激显著增加脊髓背角神经元膜表面GluA1的表达和GluA2的内化，从而促进突触AMPA受体从钙不通透(GluA2)到钙通透(GluA2缺失)的转换。这种转换将增加钙离子内流，进一步激活钙依赖的蛋白激酶，从而促进AMPA受体的磷酸化和其他磷酸化触发的活动。这种正反馈环路可能有助于应激诱导的疼痛转变的分子机制。因此，我们推测，AMPA受体磷酸化的调节和由磷酸化触发的突触AMPA受体从钙不通透到钙通透的转换是应激诱导从急性疼痛向慢性疼痛过渡的关键机制之一。为了解决这一中心假设，我们将结合足底切开和不同水平的应激来建立一个新的动物模型来研究疼痛过渡(特定目标1)，我们将在我们的疼痛过渡模型(特定目标2)中研究应激对AMPA受体活性的调节(磷酸化、运输、突触靶向和亚单位组成的变化)，并将研究磷酸化触发的AMPA受体从不透钙到通透的转换在应激诱导的疼痛过渡中的作用(特定目标3)。该方案的总体目标是建立一种新的研究疼痛过渡的动物模型，并为疼痛过渡模型的特征提供关键证据。建议的研究将证明应激产生的AMPA受体调节在从急性疼痛到慢性疼痛的转变中的作用，并为慢性手术后疼痛的发病机制提供新的线索。