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。重要的是要开发一个有用的临床前动物模型，可以复制人类疾病的复杂性。以往的研究表明，心理社会和社会环境因素参与慢性术后疼痛的发展。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，并极大地抑制了足底切口诱导的疼痛，但单独的强迫游泳应激并不产生疼痛行为;我们还发现AMPA受体GluA 1磷酸化位点Ser 831的靶向突变显著抑制应激诱导的切口疼痛延长。因此，应激可能通过调节AMPA受体的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GluA 1膜表面的表达和GluA 2的内化，从而增强突触AMPA受体开关从钙不渗透（含GluA 2）到钙渗透（缺乏GluA 2）在脊髓背角神经元。这种开关将增加Ca 2+内流并进一步激活Ca 2+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。这种正反馈回路可能有助于压力引起的疼痛转变的分子机制。因此，我们假设AMPA受体磷酸化的调节和磷酸化触发的突触AMPA受体从Ca 2+不渗透到Ca 2+渗透的转换有助于应激诱导从急性疼痛向慢性疼痛转变的关键机制。为了解决这一核心假设，来自陶博士实验室的疼痛科学家和来自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。我们将联合收割机结合不同程度的强迫游泳应激，建立一种新的动物模型来研究疼痛转变（具体目标1），我们将研究应激产生的AMPA受体活性调节（磷酸化，运输，突触靶向和亚基组成变化）在我们的疼痛转换模型（具体目标2），并且我们将研究AMPA受体的磷酸化触发的从Ca 2+不可渗透到Ca 2+可渗透的转换在应激诱导的疼痛转变中的作用（具体目标3）。本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，并提供表征疼痛转变模型的关键证据。拟议的研究将证明应激产生的AMPA受体调节在从急性疼痛向慢性疼痛的转变中的作用，并为慢性术后疼痛的发病机制提供新的线索。