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Morphine induced alterations in NMDA receptor subunit expression

吗啡诱导 NMDA 受体亚基表达的改变

基本信息

批准号：
8139158
负责人：
ROBERT M CAUDLE
金额：
$ 17.76万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8139158
关键词：
Adverse effects Animals Back Behavior Biological Assay Brain region Chronic Crime Data Disease Dose Drug abuse Exons Failure Human Hyperalgesia Imprisonment Individual Injury Mediating Methods Modeling Modification Molecular Morphine N-Methyl-D-Aspartate Receptors N-Methylaspartate NR1 gene Neuraxis Neurons Nociception Opioid Opioid Receptor Pain Pain management Pattern Pharmaceutical Preparations Play Predisposition Prisons Process Proteins RNA Splicing Rattus Recovery Resolution Risk Role Societies Spinal Cord Subgroup Substance abuse problem Symptoms Synaptic Transmission Techniques Time Variant Western Blotting Withdrawal Withdrawal Symptom Work addiction allodynia chronic pain cost interest molecular marker neuronal circuitry novel opioid abuse opioid withdrawal prevent public health relevance research study therapeutic target transmission process two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Opioids are a mainstay of modern pain therapy, yet opioid abuse has a significant negative impact on the abuser and society. It is estimated that 21% of currently incarcerated individuals are in prison because of drug related crimes. The cost to incarcerate these individuals is tens of billions of dollars per year. Since only a small percentage of opioid use results in abuse it is likely that there are some distinguishing molecular factors that may predispose an individual to opioid abuse. This project will investigate morphine induced alterations in N-methyl-D-aspartate (NMDA) receptors as one potential mechanism for predisposition to opioid abuse. NMDA receptors are intimately entwined in the processes of tolerance, withdrawal and addiction to opioids. NMDA antagonists can suppress these adverse effects of opioids. However, a single dose of an opioid is insufficient to induce significant tolerance, withdrawal or addiction indicating that time is required for some change in the NMDA receptors or neuronal circuitry to occur in order to observe these sequelae. We have found that the NR1 and NR2 subunits of NMDA receptors are highly susceptible to alterations as a result of changes in neuronal activity and that these changes in NMDA receptors may persist for an extended period of time. The altered NMDA receptors have a profound effect on behavior. Thus we hypothesize that there are changes in the splicing of NR1 subunits and changes in NR2 subunits that are induced in various regions of the CNS by morphine or morphine withdrawal. We further hypothesize that some individuals may retain these altered or "disease state" NMDA receptors long after withdrawal of the opioid, which may result in prolonged tolerance or withdrawal signs and increased susceptibility to opioid abuse. In this project we will evaluate the effects of morphine and morphine withdrawal on NR1 splice variants and NR2 subunits in various regions of the rat CNS. We will also determine if these changes persist for up to 16 weeks following the withdrawal of morphine. The NR1 and NR2 proteins will be evaluated by western blots and two-dimensional western blots and the data will be correlated to behavior in two nociceptive assays. If the data indicate that some individuals retain the disease state NMDA receptors techniques could be devised to reverse the NMDA receptor changes in an attempt to reduce the abuse susceptibility of these individuals. PUBLIC HEALTH RELEVANCE: N-methyl-D-aspartate (NMDA) receptor antagonists suppress tolerance and addiction to opioids. This project will determine if morphine treatment alters NMDA receptor subunit expression within the CNS and determine if these changes persist in a subgroup of rats. These data could provide clues to novel treatments or novel methods to prevent opioid abuse.

描述(申请人提供)：阿片类药物是现代疼痛治疗的中流砥柱，但阿片类药物滥用对滥用者和社会有重大的负面影响。据估计，目前被监禁的个人中有21%是因为与毒品有关的犯罪而入狱的。每年监禁这些人的成本高达数百亿美元。由于只有一小部分阿片类药物的使用导致滥用，很可能有一些不同的分子因素使个人容易滥用阿片类药物。本项目将研究吗啡诱导的N-甲基-D-天冬氨酸(NMDA)受体的变化，作为阿片类药物滥用易感性的一个潜在机制。NMDA受体与阿片类药物耐受、戒断、成瘾等过程密切相关。NMDA拮抗剂可以抑制阿片类药物的这些不良反应。然而，单一剂量的阿片类药物不足以诱导显著的耐受、戒断或成瘾，这表明需要时间才能使NMDA受体或神经元电路发生一些变化，以观察这些后遗症。我们发现，由于神经元活动的改变，NMDA受体的NR1和NR2亚单位非常容易发生变化，并且这些变化可能会持续一段较长的时间。NMDA受体的改变对行为有深远的影响。因此，我们假设在中枢不同区域存在由吗啡或吗啡戒断引起的NR1亚基和NR2亚基剪接的变化。我们进一步假设，一些人可能在停用阿片类药物后很长一段时间内仍保留着这些改变的或“疾病状态”的NMDA受体，这可能会导致更长的耐受或戒断迹象，并增加对阿片类药物滥用的敏感性。在这个项目中，我们将评估吗啡和吗啡戒断对大鼠中枢不同区域NR1剪接变异体和NR2亚基的影响。我们还将确定在停用吗啡后，这些变化是否会持续长达16周。NR1和NR2蛋白将通过Western blotts和二维Western blotts进行评估，数据将与两种伤害性测试中的行为相关联。如果数据表明一些人保持了疾病状态，就可以设计NMDA受体技术来逆转NMDA受体的变化，试图降低这些人的滥用易感性。公共卫生相关性：N-甲基-D-天冬氨酸(NMDA)受体拮抗剂抑制对阿片类药物的耐受性和成瘾。该项目将确定吗啡治疗是否改变了中枢神经系统内NMDA受体亚单位的表达，并确定这些变化是否在一组大鼠中持续存在。这些数据可能为预防阿片类药物滥用的新治疗或新方法提供线索。