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）：对研究的需求压倒性，从而使中枢神经系统机制有更深入的了解，这些机制调节了从急性到慢性疼痛的过渡。医学研究所指出，有1.16亿美国人的慢性疼痛负担，每年耗资超过6亿美元。虽然通常规定了阿片类药物以治疗疼痛，但它们只是中等有效的，不利的副作用和滥用的潜力，强调需要对其镇痛机制进行更多了解。大量研究表明，周围炎症会引起脊髓和大脑内的不良适应性可塑性，称为中心敏化，这会导致慢性疼痛。但是，数据表明，中央敏化的数据远远超过了疼痛敏感性的明显迹象，以“潜在的中央 （LCS）。该提案具有创新性，因为它表明了LCS的新分子机制；中心假设是，炎症会产生腺苷酸环化酶1（AC1）（AC1） - AMPA受体（AMPAR）和依赖性LC，依赖于脊柱阿片类阿片类药物的作用，这是脊柱阿片类接受的。在损伤后长期LC中，MU阿片受体（MOR）的活性降低了背角AMPAR介导的Ca2+信号传导，AIM 1使用创新的实时Ca2+成像成年的脊柱背角（DH）切片，以确定阿片类受体阻断是否会增加AMPAR介导的dh CA2+ ampar ampar ampar ampar ampar。维持LCS。在具有AC1缺失或药理抑制的小鼠的DH中，AIM 3将比较AMPAR介导的Ca2+反应，并在存在或不存在阿片类受体阻断的情况下确定总和磷酸化的GLUA2和细胞表面表达。拟议的研究很重要，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以释放引起摄影性的AC1-Ampar信号，从而使过渡到慢性疼痛。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，并且具有揭示新目标的长期潜力 防止从急性到慢性疼痛的过渡。