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: 8862455
• 负责人: Feng Tao
• 金额: $ 37万
• 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: 2014-12-02 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8862455
• 关键词: AMPA Receptors; Acids; Acute; Address; Animal Model; Animals; Chronic; Complex; Development; Environmental Risk Factor; Event; Feedback; Goals; Hormones; Human; Laboratories; Light; Long-Term Potentiation; Mediating; Membrane; Modeling; Molecular; Mutant Strains Mice; Mutation; N-Methyl-D-Aspartate Receptors; Neuronal Plasticity; Nociception; Operative Surgical Procedures; Oral 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; Scientist; Spinal; Spinal Cord; Stress; Surface; Surgical incisions; Swimming; Synapses; Work; central sensitization; chronic pain; experience; 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, pain scientists from Dr. Tao's laboratory and non-pain neuroscientists with expertise in neuroplasticity from Dr. Huganir's laboratory will work together. We will combine plantar incision with different levels of forced swim 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 to study pain transition 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（通过应用程序提供）：从急性到慢性疼痛的过渡可能是由机制的复杂组合造成的。建立一个有用的临床前动物模型很重要，该模型可以复制人类状况的复杂性。先前的研究表明，慢性术后疼痛的发展涉及社会心理和社会环境因素。在我们的初步研究中，我们发现强迫游泳压力显着增强了足底切口诱导的 - 氨基-3-羟基-5-羟基-5-甲基-4-甲基-4-异沙唑嗜酸果酸（AMPA）受体磷酸化（AMPA）受体磷酸化，并且大大延长了足底切口诱发的疼痛，但单独的游泳压力不会产生疼痛的疼痛行为；我们还发现，靶向AMPA受体GLUA1光基化位点Ser831的靶向突变显着抑制压力引起的切口疼痛的延长。这是通过控制AMPA受体磷酸化来诱导疼痛转变的压力。最近，我们进一步发现，强迫游泳应力显着增加了GLUA1膜表面表达和GLUA2内在化，从而增强了从Ca2+可耐受性（含GLUA2的）转换到脊柱背角神经元中的CA2+可耐受性（GLUA2）到CA2+可渗透（GLUA2-lacking）。该开关将增加Ca2+影响，并进一步激活Ca2+依赖性蛋白激酶，从而促进AMPA受体磷酸化和其他磷酸化触发的活性。这种积极的反馈回路可能有助于分子机制，这些机制是压力引起的疼痛转变的基础。因此，我们假设调节AMPA受体磷酸化和磷酸化触发的突触AMPA受体的转换从Ca2+可耐受到Ca2+可渗透性的转换有助于应激诱导从急性到慢性疼痛的过渡。为了解决这一中心假设，陶博士的实验室和非虐待神经科学家的疼痛科学家在Huganir博士的实验室中具有神经可塑性的专业知识，将共同努力。 We will combine plantar incision with different levels of forced swim 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 photophosphorylation-triggered switch of AMPA receivers from Ca2+ - 可抗应力诱导的疼痛转变的Ca2+ - 可渗透（特定目标3）。该提案的总体目标是开发一种新的动物模型来研究疼痛过渡并提供关键证据以表征疼痛过渡模型。拟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过渡中的作用，并为慢性术后疼痛发病而开发了新的启示。