Morphine/NMDA interactions: Antinociceptive and discriminative stimulus effects

吗啡/NMDA 相互作用：镇痛和辨别刺激作用

• 批准号: 7327979
• 负责人: Bradford D Fischer
• 金额: $ 2.03万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2008-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7327979
• 关键词: Absence of pain sensation; Acute; Agreement; Analgesics; Animal Model; Attention; Attenuated; Behavior assessment; Behavioral; Brain; Chronic; Clinical; Clinical Trials; Condition; D Aspartate; Data; Development; Discrimination; Disruption; Drug Delivery Systems; Drug abuse; End Point; Essential Genes; Genes; Genetic; Genetic Models; Glutamates; Investigation; Laboratories; Lead; Mediating; Monkeys; Morphine; Morphine Dependence; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; NR1 NMDA receptor; NR1 gene; Nature; Opioid; Pain; Perception; Play; Procedures; Rattus; Reporting; Role; Stimulus; System; Testing; Thinking; clinically relevant; design; drug discrimination; human NR1 protein; improved; novel; receptor function; research study; transmission process

DESCRIPTION (provided by applicant): There is now significant evidence that NMDA glutamate transmission is involved in the behavioral effects of morphine. For example, inhibition of NMDA receptors alters the antinociceptive and discriminative stimulus effects of morphine, and tolerance to these effects under certain conditions. The ability of NMDA receptor inactivation to alter morphine's effects has attracted significant clinical attention. Currently, drugs that target the NMDA receptor are in clinical trials for their ability to improve morphine analgesia and as treatments for morphine dependence. To date, manipulations for assessing NMDA receptor involvement in the behavioral effects of morphine have been limited to pharmacological inhibition of the NMDA receptor. The proposed study further examines the role of NMDA receptors in the behavioral effects of morphine in mice with a partial deletion in the gene encoding the NR1 subunit of the NMDA receptor (NR1-KD). The aim of the current proposal is to assess NMDA receptor involvement on behavioral endpoints related to morphine analgesia and the subjective effects of morphine that are thought to contribute to abuse. Specifically, these studies systematically assess morphine antinociception and the discriminative stimulus effects of morphine in a genetic model of NMDA deficiency. Specific Aim I tests the hypothesis that disruption of NMDA receptor function alters the antinociceptive effects of morphine after acute and chronic morphine administration in NR1-KD mice, enhancing our understanding of NMDA-mediated mechanisms in morphine analgesia. Specific Aim II tests the hypothesis that the NMDA system plays a role in the discriminative stimulus effects of morphine, enhancing our understanding of NMDA-mediated mechanisms in the subjective effects of morphine. The experiments detailed in this proposal will provide novel data concerning NMDA receptor mechanisms in clinically relevant behavioral effects of morphine. Together, these investigations are designed to systematically assess NMDA receptor involvement in the analgesic effects of morphine as well as morphine's subjective effects that are thought to contribute to its abuse. Findings from these experiments may have important clinical implications, and may lead to new pharmacotherapeutic strategies in the treatment of pain and drug abuse.

描述（由申请人提供）：现在有重要证据表明 NMDA 谷氨酸传输与吗啡的行为效应有关。例如，抑制 NMDA 受体会改变吗啡的镇痛和辨别刺激作用，以及在某些条件下对这些作用的耐受性。 NMDA 受体失活改变吗啡作用的能力引起了临床的广泛关注。目前，针对 NMDA 受体的药物正在临床试验中，因为它们能够改善吗啡镇痛并治疗吗啡依赖。迄今为止，评估 NMDA 受体参与吗啡行为效应的操作仅限于 NMDA 受体的药理学抑制。这项拟议的研究进一步研究了 NMDA 受体在吗啡对编码 NMDA 受体 NR1 亚基（NR1-KD）基因部分缺失的小鼠的行为影响中的作用。当前提案的目的是评估 NMDA 受体对吗啡镇痛相关行为终点的参与以及吗啡被认为导致滥用的主观影响。具体来说，这些研究系统地评估了吗啡的镇痛作用以及吗啡在 NMDA 缺乏遗传模型中的辨别刺激作用。具体目标 I 测试了以下假设：在 NR1-KD 小鼠中急性和慢性吗啡给药后，NMDA 受体功能的破坏会改变吗啡的镇痛作用，从而增强我们对 NMDA 介导的吗啡镇痛机制的理解。 Specific Aim II 检验了 NMDA 系统在吗啡的辨别刺激效应中发挥作用的假设，增强了我们对 NMDA 介导的吗啡主观效应机制的理解。本提案中详述的实验将提供有关吗啡临床相关行为效应中 NMDA 受体机制的新数据。总之，这些研究旨在系统地评估 NMDA 受体参与吗啡的镇痛作用以及吗啡的主观作用（被认为有助于其滥用）。这些实验的结果可能具有重要的临床意义，并可能导致治疗疼痛和药物滥用的新药物治疗策略。