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治疗的支柱，但阿片类药物滥用对滥用者和社会产生重大负面影响。据估计，目前被监禁的人中有 21% 是因为与毒品有关的犯罪而入狱的。监禁这些人的成本每年高达数百亿美元。由于只有一小部分阿片类药物的使用会导致滥用，因此可能存在一些独特的分子因素可能导致个体容易滥用阿片类药物。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，作为阿片类药物滥用倾向的一种潜在机制。 NMDA 受体与阿片类药物的耐受、戒断和成瘾过程密切相关。 NMDA 拮抗剂可以抑制阿片类药物的这些副作用。然而，单剂量的阿片类药物不足以诱导显着的耐受性、戒断或成瘾，这表明需要时间使 NMDA 受体或神经元回路发生某些变化才能观察到这些后遗症。我们发现，NMDA 受体的 NR1 和 NR2 亚基非常容易因神经元活动的变化而发生变化，并且 NMDA 受体的这些变化可能会持续很长一段时间。 NMDA 受体的改变对行为产生深远的影响。因此，我们假设吗啡或吗啡戒断会在中枢神经系统的各个区域诱导 NR1 亚基剪接的变化和 NR2 亚基的变化。我们进一步假设，一些个体在阿片类药物戒断后很长时间内可能保留这些改变的或“疾病状态”的 NMDA 受体，这可能导致长期耐受或戒断症状，​​并增加对阿片类药物滥用的易感性。在本项目中，我们将评估吗啡和吗啡戒断对大鼠 CNS 各个区域 NR1 剪接变异体和 NR2 亚基的影响。我们还将确定这些变化是否会在吗啡戒断后持续长达 16 周。 NR1 和 NR2 蛋白将通过蛋白质印迹和二维蛋白质印迹进行评估，并且数据将与两种伤害性测定中的行为相关。如果数据表明某些个体保留了 NMDA 受体疾病状态，则可以设计逆转 NMDA 受体变化的技术，以试图降低这些个体的滥用易感性。 公共卫生相关性：N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂可抑制阿片类药物的耐受性和成瘾性。该项目将确定吗啡治疗是否会改变中枢神经系统内 NMDA 受体亚基的表达，并确定这些变化是否在一组大鼠中持续存在。这些数据可以为防止阿片类药物滥用的新疗法或新方法提供线索。