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: 8652959
• 负责人: Susan M Carlton
• 金额: $ 54.34万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652959
• 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.

描述(申请人提供)：突然戒断或停用鸦片类药物会导致一系列严重的不良症状，使药物依赖者继续渴望鸦片类药物。戒断症状的核心之一是疼痛敏感度的增加(疼痛敏感化或痛敏)。这种疼痛敏感化是由于突触的可塑性，特别是在脊髓和初级传入神经元。最近的证据表明，海马区突触可塑性的潜在机制也可能发生在脊髓中。尽管急性接触阿片类药物可能会引起痛敏，但长期或重复使用阿片类药物会促进阿片类药物引起的痛敏的程度和持续时间，并可能扩大引起痛敏的解剖部位。阿片类药物诱导的慢性痛敏的持续性与阿片类药物依赖的细胞机制是一致的，这种机制只在反复接触药物后才会发展。已有研究表明，AMPA谷氨酸受体在脊髓内的转运与疼痛敏感性的形成有关。同样，海马谷氨酸能系统被认为与阿片类药物诱导的神经元和行为可塑性有关。我们建议在三个不同的水平上记录在阿片类药物依赖和疼痛敏感性中AMPA受体表达的平行变化：1)海马区，2)脊髓和3)初级传入神经元。拟议的实验将检验这样一种假设，即急性戒断重复注射吗啡会通过改变AMPA受体的突触表达和组成而导致感觉敏化，并且AMPA受体的这种神经可塑性类似于慢性炎症性疼痛。在具体目标1中，我们将描述在吗啡戒断模型中发展的感觉敏化，并将其与在慢性炎症性疼痛模型中发展的敏化进行比较。在具体目标2中，我们将分析吗啡戒断相关敏化过程中AMPA受体亚单位(GluR1/2/3)表达和组成的动态变化，并将其与慢性炎症性疼痛的表达和组成进行比较。在具体目标3中，我们将表征吗啡戒断相关感觉敏化作用下的AMPA受体突触的神经可塑性，并将其与慢性炎症性疼痛的AMPA受体神经可塑性进行比较。在特定的目标4中，我们将证明AMPA拮抗剂的治疗既缓解了吗啡戒断相关的感觉敏感化，也缓解了与慢性炎症性疼痛相关的感觉敏感化。这些研究具有重要意义，因为它们将阐明阿片类成瘾者和炎症性疼痛患者共有的关键谷氨酸能适应不良变化。总体而言，这些研究将提供对神经可塑性的洞察，这可能导致药物治疗干预阿片类成瘾者疼痛的新方法。