AMPA receptors: Common role in opiate withdrawal and pain sensitivity

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，使药物依赖者持续渴望阿片类药物。戒断症状的核心之一是疼痛敏感性的增加（疼痛敏感或痛觉过敏）。这种疼痛敏化是由于突触的可塑性，特别是在脊髓和初级传入神经。最近的证据表明，海马突触可塑性的机制也可能发生在脊髓中。虽然急性暴露于阿片类药物可引起痛觉过敏，但慢性或反复给药可促进阿片类药物引起的痛觉过敏的程度和持续时间，并可能扩大引起痛觉过敏的解剖部位。慢性阿片类药物引起的痛觉过敏的持续存在与阿片类药物依赖的细胞机制是一致的，只有在反复接触药物后才会发展。研究表明，脊髓内AMPA谷氨酸受体的转运参与了疼痛敏感性的发展。类似地，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。我们拟在三个不同的水平上记录阿片依赖和疼痛敏感中AMPA受体表达的平行变化：1)海马，2)脊髓和3)初级传入神经元。该实验将验证反复吗啡给药的急性戒断通过改变AMPA受体的突触表达和组成导致感觉敏化的假设，并且AMPA受体的神经可塑性与潜在的慢性炎症性疼痛相似。在具体目标1中，我们将描述在吗啡戒断模型中产生的感觉致敏，并将其与慢性炎症性疼痛模型中产生的致敏进行比较。在Specific Aim 2中，我们将分析吗啡戒断相关致敏过程中AMPA受体亚单位（GluR1/2/3）的表达和组成的动态变化，并将其与慢性炎症性疼痛进行比较。在Specific Aim 3中，我们将描述吗啡戒断相关感觉敏化背后的AMPA受体突触的神经可塑性，并将其与慢性炎症性疼痛背后的AMPA受体神经可塑性进行比较。在Specific Aim 4中，我们将证明用AMPA拮抗剂治疗可以缓解吗啡戒断相关的感觉敏化以及与慢性炎症性疼痛相关的感觉敏化。这些研究具有重要意义，因为它们将阐明阿片类药物成瘾者和炎症性疼痛患者共同存在的关键谷氨酸能适应不良变化。总的来说，这些研究将提供对神经可塑性的深入了解，这可能会导致药物治疗干预阿片类成瘾者疼痛治疗的新方法。

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.