Morphine induced alterations in NMDA receptor subunit expression

吗啡诱导 NMDA 受体亚基表达的改变

• 批准号: 8009045
• 负责人: ROBERT M CAUDLE
• 金额: $ 17.15万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009045
• 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

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（由申请人提供）：阿片类药物是现代疼痛疗法的支柱，但是阿片类药物滥用对施虐者和社会产生了重大负面影响。据估计，由于与毒品有关的犯罪，目前有21％的目前被监禁的人入狱。监禁这些人的费用是每年数十亿美元。由于只有一小部分阿片类药物的使用会导致滥用，因此很可能有一些明显的分子因素可能使人遭受阿片类药物滥用。该项目将研究吗啡诱导的N-甲基-D-天冬氨酸（NMDA）受体的改变，这是易受阿片类药物滥用的潜在机制。 NMDA受体在耐受性，戒断和对阿片类药物成瘾的过程中紧密纠缠。 NMDA拮抗剂可以抑制阿片类药物的这些不良反应。但是，单剂量的阿片类药物不足以诱导明显的公差，戒断或成瘾，这表明在NMDA受体或神经元电路中发生某些变化所需的时间才能观察到这些后遗症。我们发现，由于神经元活性的变化，NMDA受体的NR1和NR2亚基非常容易受到改变，并且NMDA受体的这些变化可能会长时间持续存在。变化的NMDA受体对行为有深远的影响。因此，我们假设NR1亚基的剪接发生了变化，以及吗啡或吗啡戒断在CNS的各个区域诱导的NR2亚基的变化。我们进一步假设，有些人可能在阿片类药物撤离后很长时间保留这些变化或“疾病状态” NMDA受体，这可能会导致耐受性延长或戒断迹象，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神经系统各个区域中NR1剪接变体和NR2亚基的影响。我们还将确定吗啡撤离后，这些变化是否持续长达16周。 NR1和NR2蛋白将通过Western印迹和二维Western印迹进行评估，并且数据将与两种伤害性测定法中的行为相关。如果数据表明某些人可以保留疾病状态NMDA受体技术来扭转NMDA受体的变化，以减少这些个体的滥用敏感性。 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受体亚基的表达，并确定这些变化是否在大鼠亚组中持续存在。这些数据可以为防止阿片类药物滥用的新型治疗方法或新方法提供线索。