Gender differences in stress-induced pain transition after surgery

手术后压力引起的疼痛转变的性别差异

• 批准号: 8992106
• 负责人: Feng Tao
• 金额: $ 10万
• 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/8992106
• 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; Sex Characteristics; 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（由申请人提供）：从急性疼痛到慢性疼痛的转变可能是由复杂的机制组合引起的。开发一种可以复制人类状况复杂性的有用的临床前动物模型非常重要。先前的研究表明，心理社会和社会环境因素与慢性术后疼痛的发展有关。在我们的初步研究中，我们发现强迫游泳应激显着增强足底切口诱导的β-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体磷酸化，并大大延长足底切口诱导的疼痛，但单独强迫游泳应激不会产生疼痛行为；我们还发现，AMPA 受体 GluA1 磷酸化位点 Ser831 的靶向突变可显着抑制应激引起的切口疼痛的延长。因此，压力可能通过调节 AMPA 受体磷酸化来诱导疼痛转变。最近，我们进一步发现强迫游泳应激显着增加GluA1膜表面表达和GluA2内化，从而增强脊髓背角神经元中突触AMPA受体从Ca2+不可渗透（含有GluA2）到Ca2+渗透（缺乏GluA2）的转变。这种开关将增加 Ca2+ 流入并进一步激活 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动。这种正反馈循环可能有助于压力引起的疼痛转变的分子机制。因此，我们推测 AMPA 受体磷酸化的调节以及磷酸化触发的突触 AMPA 受体从 Ca2+ 不可渗透性到 Ca2+ 可渗透性的转变有助于压力诱导从急性疼痛转变为慢性疼痛的关键机制。为了解决这一中心假设，陶博士实验室的疼痛科学家和胡加尼尔博士实验室的具有神经可塑性专业知识的非疼痛神经科学家将共同努力。我们将足底切口与不同水平的强迫游泳压力相结合，开发一种新的动物模型来研究疼痛转变（具体目标1），我们将在我们的疼痛转变模型中研究压力产生的AMPA受体活性调节（磷酸化、运输、突触靶向和亚基组成变化）（具体目标2），我们将研究磷酸化触发的AMPA受体从Ca2+不渗透性转变的作用 在压力引起的疼痛转变中向 Ca2+- 渗透（具体目标 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转变，并提供关键证据来表征疼痛转变模型。拟议的研究将证明压力产生的 AMPA 受体调节在急性疼痛向慢性疼痛转变中的作用，并为慢性术后疼痛的发病机制提供新的线索。