Morphine/NMDA interactions: Antinociceptive and discriminative stimulus effects

描述（由申请人提供）：现在有重要的证据表明，NMDA谷氨酸传输参与吗啡的行为效应。例如，NMDA受体的抑制改变了吗啡的抗伤害性和辨别性刺激作用，以及在某些条件下对这些作用的耐受性。NMDA受体失活改变吗啡效应的能力已经引起了临床的显著关注。目前，靶向NMDA受体的药物正处于临床试验中，因为它们能够改善吗啡镇痛和治疗吗啡依赖。迄今为止，用于评估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。该研究进一步研究了NMDA受体在吗啡对小鼠行为影响中的作用，其中部分缺失了编码NMDA受体NR 1亚基的基因（NR 1-KD）。目前的建议的目的是评估NMDA受体参与的行为终点有关的吗啡镇痛和吗啡的主观影响，被认为是有助于滥用。具体而言，这些研究系统地评估吗啡的抗伤害性和歧视性刺激的影响，吗啡在NMDA缺乏症的遗传模型。具体目的我测试的假设，NMDA受体功能的破坏改变了急性和慢性吗啡给药后，在NR 1-KD小鼠吗啡的镇痛作用，提高我们的理解NMDA介导的机制在吗啡镇痛。具体目标II测试的假设，NMDA系统在吗啡的歧视性刺激效应中发挥作用，提高我们对NMDA介导的机制在吗啡的主观效果的理解。本实验将为吗啡临床相关行为效应中NMDA受体机制的研究提供新的数据。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被认为有助于其滥用的吗啡的主观效应。这些实验的结果可能具有重要的临床意义，并可能导致新的药物治疗策略在治疗疼痛和药物滥用。

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.