AMPA receptors: Common role in opiate withdrawal and pain sensitivity

AMPA 受体：在阿片戒断和疼痛敏感性中的常见作用

• 批准号: 8071241
• 负责人: Susan M Carlton
• 金额: $ 53.57万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071241
• 关键词: AMPA Receptors; Abstinence; Acute; Address; Adult; Adverse effects; Afferent Neurons; Animals; Area; Behavior Disorders; Behavioral; Behavioral Symptoms; Biochemical; Brain; Cells; Chronic; Chronic inflammatory pain; Clinical Research; Clinical Treatment; Cutaneous; Data; Development; Drug Addiction; Drug abuse; Exposure to; Fiber; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Hyperalgesia; In Vitro; Individual; Intervention; Lead; Left; Link; Mechanics; Mediating; Membrane; Modeling; Molecular; Morphine; Neurobiology; Neuronal Plasticity; Neurons; Opiate Addiction; Opiates; Pain; Pain management; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Regulation; Relapse; Research; Role; Sensory; Series; Site; Spinal; Spinal Cord; Spinal cord posterior horn; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Syndrome; System; Testing; Thermal Hyperalgesias; Withdrawal; Withdrawal Symptom; addiction; allodynia; base; chronic pain; clinically relevant; craving; improved; in vivo; inflammatory pain; innovation; insight; neurobiological mechanism; neurotransmission; novel; novel strategies; public health relevance; receptor expression; research study; success; trafficking

DESCRIPTION (provided by applicant): Abrupt abstinence or withdrawal from opiate drugs causes a series of severe adverse symptoms, which keep drug-dependent individuals craving continued opiates. One of the core of withdrawal symptoms is an increase in pain sensitivity (pain sensitization or hyperalgesia). This pain sensitization is due to synaptic plasticity, particularly in the spinal cord and primary afferents. Recent evidence suggests that mechanisms underlying synaptic plasticity in the hippocampus may also occur in the spinal cord. Although acute exposure to opiates may induce hyperalgesia, chronic or repeated administration of the drug facilitate the magnitude and duration of opiate-induced hyperalgesia, and may expand the anatomical sites at which hyperalgesia is induced. Persistence of chronic opiate-induced hyperalgesia is consistent with cellular mechanisms of opiate dependence that only develop after repeated exposure to the drug. It has been demonstrated that AMPA glutamate receptor trafficking within the spinal cord is involved in the development of pain sensitivity. Similarly, hippocampal glutamatergic systems are thought to be involved in opiate-induced neuronal and behavioral plasticity. We propose to document the parallel changes in AMPA receptor expression occurring in opiate dependence and pain sensitivity at three different levels: 1) hippocampus, 2) spinal cord and 3) primary afferent neurons. The proposed experiments will test the hypothesis that acute withdrawal from repeated morphine administration results in sensory sensitization by altering synaptic expression and composition of AMPA receptors and that this neuroplasticity in AMPA receptors is similar to that underlying chronic inflammatory pain. In Specific Aim 1 we will characterize the sensory sensitization that develops in a model of morphine withdrawal and compare it to the sensitization that develops in a model of chronic inflammatory pain. In Specific Aim 2 we will analyze the dynamic changes in expression and composition of AMPA receptor subunits (GluR1/2/3) in morphine withdrawal-associated sensitization and compare them to those occurring in chronic inflammatory pain. In Specific Aim 3 we will characterize the neuroplasticity in AMPA receptor synapses underlying morphine withdrawal-associated sensory sensitization and compare it to the AMPA receptor neuroplasticity underlying chronic inflammatory pain. In Specific Aim 4 we will demonstrate that treatment with AMPA antagonists relieves both morphine withdrawal-associated sensory sensitization as well as that associated with chronic inflammatory pain. These studies are significant because they will elucidate key glutamatergic maladaptive changes that opiate addicts and inflammatory pain patients have in common. Overall, these studies will provide insight into the neuroplasticity that may lead to novel approaches for pharmacotherapeutic intervention for pain treatment in opiate addicts. PUBLIC HEALTH RELEVANCE: The experiments proposed in this application will address the question of how drug-induced alterations in the hippocampus, spinal cord and primary afferents contribute to enhanced sensory sensitivity in opiate addicts. These results will enhance our understanding of the synaptic molecular and membrane mechanisms underlying this adverse effect of drug dependence and will help us to improve pain management in opiate addicts.

描述（由申请人提供）：突然戒断或戒断阿片类药物会引起一系列严重的不良症状，使药物依赖者继续渴望阿片类药物。戒断症状的核心之一是疼痛敏感性增加（疼痛敏感或痛觉过敏）。这种疼痛敏感化是由于突触可塑性，特别是在脊髓和初级传入神经中。最近的证据表明，海马中突触可塑性的潜在机制也可能发生在脊髓中。虽然急性暴露于阿片类药物可能会诱导痛觉过敏，慢性或重复给药的药物促进阿片类药物诱导的痛觉过敏的幅度和持续时间，并可能扩大痛觉过敏诱导的解剖部位。慢性阿片类药物诱导的痛觉过敏的持续性与阿片类药物依赖的细胞机制一致，这种机制仅在反复暴露于药物后才发生。已经证明脊髓内AMPA谷氨酸受体的运输参与疼痛敏感性的发展。类似地，海马神经元能系统被认为参与阿片诱导的神经元和行为可塑性。我们建议记录阿片依赖和疼痛敏感性中AMPA受体表达在三个不同水平发生的平行变化：1）海马，2）脊髓和3）初级传入神经元。拟议的实验将检验这样的假设：重复给予吗啡后急性戒断会通过改变AMPA受体的突触表达和组成而导致感觉敏感化，并且AMPA受体的这种神经可塑性与慢性炎症性疼痛的潜在神经可塑性相似。在具体目标1中，我们将描述吗啡戒断模型中产生的感觉致敏作用，并将其与慢性炎性疼痛模型中产生的致敏作用进行比较。在具体目标2中，我们将分析吗啡戒断相关致敏中AMPA受体亚基（GluR 1/2/3）表达和组成的动态变化，并将其与慢性炎性疼痛中发生的变化进行比较。在具体目标3中，我们将描述吗啡戒断相关感觉敏化的AMPA受体突触的神经可塑性，并将其与慢性炎性疼痛的AMPA受体神经可塑性进行比较。在具体目标4中，我们将证明AMPA拮抗剂治疗可缓解吗啡戒断相关的感觉敏化以及与慢性炎性疼痛相关的感觉敏化。这些研究意义重大，因为它们将阐明阿片类成瘾者和炎性疼痛患者共有的关键性神经元适应不良变化。总的来说，这些研究将提供深入了解神经可塑性，可能导致阿片类药物成瘾者疼痛治疗的药物干预的新方法。 公共卫生关系：本申请中提出的实验将解决药物诱导的海马、脊髓和初级传入神经改变如何有助于阿片成瘾者增强感觉敏感性的问题。这些结果将增强我们对药物依赖不良反应背后的突触分子和膜机制的理解，并将有助于我们改善阿片类药物成瘾者的疼痛管理。