Spinal AMPA receptors, latent central sensitization and chronic pain

脊髓 AMPA 受体、潜在中枢敏化和慢性疼痛

• 批准号: 8772240
• 负责人: Suzanne Doolen
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772240
• 关键词: AMPA Receptors; Acute; Adult; Adverse effects; American; Analgesics; Automobile Driving; Behavior; Behavioral; Brain; CTOP; Calcium; Cell surface; Complex; Data; Development; Equilibrium; Event; Freund' s Adjuvant; Glutamates; Healed; Healthcare; Hyperalgesia; Image; Inflammation; Inflammatory; Injury; Institute of Medicine (U.S.); Lead; Light; Masks; Measures; Mediating; Methods; Mission; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Naltrexone; Neuraxis; Neurons; Nociception; Olives - dietary; Opioid; Opioid Receptor; Pain; Pain management; Paper; Peripheral; Permeability; Pharmaceutical Preparations; Phosphorylation; Posterior Horn Cells; Process; Public Health; Receptor Activation; Receptor Signaling; Reporting; Research; Science; Signal Transduction; Slice; Spinal; Spinal Cord; Stress; Synapses; System; Testing; Therapeutic Intervention; Time; Tissues; adenylyl cyclase 1; central sensitization; chronic pain; cost; density; dorsal horn; healing; innovation; mu opioid receptors; neurochemistry; neurophysiology; novel; novel therapeutic intervention; pain inhibition; prevent; public health relevance; receptor function; response; trafficking

DESCRIPTION (provided by applicant): There is an overwhelming need for research leading to a greater understanding of central nervous system mechanisms that regulate the transition from acute to chronic pain. The Institute of Medicine states that 116 million Americans are burdened with chronic pain, costing over $600 billion annually. While opioid medications are commonly prescribed to treat pain, they are only moderately efficacious, and adverse side effects and potential for abuse stress the need for greater understanding of their analgesic mechanisms. A large body of research indicates that peripheral inflammation initiates maladaptive plasticity within the spinal cord and brain, termed central sensitization-that contributes to chronic pain. Less appreciated, however, are data which suggest that central sensitization far outlasts overt signs of pain sensitivity, in a silent form termed "latent central sensitization" (LCS). This proposal is innovative in that it suggests a novel molecular mechanism of LCS; the central hypothesis is that inflammation produces an adenylyl cyclase 1 (AC1)- and AMPA receptor (AMPAR)-dependent LCS that is masked by spinal opioid receptors. This hypothesis will be tested with three specific aims: AIM 1 tests the hypothesis that tonic mu opioid receptor (MOR) activity decreases dorsal horn AMPAR-mediated Ca2+ signaling during long-lasting LCS after injury. Aim 1 uses innovative real-time Ca2+ imaging in adult spinal dorsal horn (DH) slices to determine whether opioid receptor blockade increases AMPAR-mediated DH Ca2+ signaling. AIM 2 tests the hypothesis that AMPAR subunit GluA2 phosphorylation and internalization maintains LCS. Aim 2 will test this hypothesis by measuring GluA2 Ser880 phosphorylation and internalization in the presence or absence of NTX. AIM 3 tests the hypothesis that injury-induced long- term increases in GluA2 internalization and Ca2+ permeability are maintained by AC1 activity. In DH from mice with AC1 deletion or pharmacological inhibition, Aim 3 will compare AMPAR-mediated Ca2+ responses and determine total and phosphorylated GluA2 and cell surface expression in the presence or absence of opioid receptor blockade. The proposed research is significant because if our hypotheses are correct, then any event that interferes with opioid receptor activity could unleash pronociceptive AC1-AMPAR signaling, and thus allow the transition to chronic pain. The results and concepts generated in this proposal may lead to a vertical leap in our understanding of pain vulnerability after tissue inflammation, and has the long-term potential to reveal novel targets to prevent the transition from acute to chronic pain.

描述（由申请人提供）：迫切需要进行研究以更好地了解调节从急性疼痛到慢性疼痛转变的中枢神经系统机制。美国医学研究所指出，1.16 亿美国人承受着慢性疼痛的困扰，每年造成的损失超过 6000 亿美元。虽然阿片类药物通常用于治疗疼痛，但它们的疗效有限，而且不良副作用和滥用的可能性强调需要更好地了解其镇痛机制。大量研究表明，周围炎症会引发脊髓和大脑内的适应不良可塑性，称为中枢敏化，从而导致慢性疼痛。然而，不太受重视的数据表明，中枢敏化远远超过了疼痛敏感的明显迹象，以一种称为“潜在中枢”的无声形式存在。 该提案的创新之处在于它提出了 LCS 的一种新的分子机制；中心假设是炎症产生腺苷酸环化酶 1 (AC1) 和 AMPA 受体 (AMPAR) 依赖性 LCS，而这种 LCS 被脊髓掩盖该假设将通过三个具体目标进行测试： AIM 1 测试强效 mu 阿片受体 (MOR) 活性会降低背角 AMPAR 介导的 Ca2+ 信号传导的假设。 Aim 1 在成人脊髓背角 (DH) 切片中使用创新的实时 Ca2+ 成像来确定阿片受体阻断是否会增加 AMPAR 介导的 DH Ca2+ 信号传导，AIM 2 测试了 AMPAR 亚基 GluA2 磷酸化和Aim 2 将通过在存在或不存在 NTX 的情况下测量 GluA2 Ser880 磷酸化和内化来检验这一假设。图3检验了这样的假设：损伤引起的GluA2内化和Ca2+渗透性的长期增加是由AC1活性维持的。在 AC1 缺失或药物抑制的小鼠 DH 中，Aim 3 将比较 AMPAR 介导的 Ca2+ 反应，并确定在存在或不存在阿片受体阻断的情况下总的和磷酸化的 GluA2 以及细胞表面表达。这项研究意义重大，因为如果我们的假设正确，那么任何干扰阿片受体活性的事件都可能释放促痛性 AC1-AMPAR 信号，从而转变为慢性疼痛。该提案中产生的结果和概念可能会导致我们对组织炎症后疼痛脆弱性的理解发生垂直飞跃，并具有揭示新目标的长期潜力。 防止从急性疼痛转变为慢性疼痛。