A Novel Mechanism for Decreasing Opioid Reward

项目摘要 过多的谷氨酸信号通过N-甲基-D-天冬氨酸受体(NMDAR)参与了改变 与阿片类药物奖赏和依赖相关的神经元可塑性形式。当前的尖端基础知识 研究奖建议在功能上解偶联NMDAR激活下游的信号复合体，以 消除异常的NMDAR依赖的一氧化氮信号，并绕过阿片类奖赏的发展。 在美国，处方药过量导致的意外死亡人数自那以来增加了两倍多 1990年，比可卡因和海洛因造成的死亡总和还要多。非故意药物的增加 过量死亡率主要是由于阿片类镇痛剂的使用增加所致。治疗不充分 疼痛，由于不完全的止痛效果和滥用麻醉剂的倾向而加剧，导致药物不断攀升 使用，造成的社会经济成本估计为每年6,000亿美元。提高安全性、有效性、副作用 因此，阿片类镇痛剂的效果概况和滥用倾向仍然是医学上的迫切需要。NMDAR过多 刺激触发涉及神经元型一氧化氮合酶激活的信号级联反应 (NNOS)，它催化信号分子一氧化氮(NO)的形成，促进成瘾- 相关行为。抑制异常谷氨酸能高兴奋性和抑制nNOS减少 临床前研究中的成瘾相关行为。然而，NMDA受体的治疗潜力 拮抗剂和一氧化氮合酶抑制剂受到严重副作用的限制。我们建议在功能上脱钩 NMDAR从nNOS信号转导到规避阿片类药物奖励，而没有全球NMDAR的不良副作用 拮抗剂或非选择性一氧化氮合酶催化抑制剂。我们建议通过有选择地实现这一目标 破坏nNOS和突触后密度95kDA之间的蛋白质-蛋白质界面 它将nNOS与NMDAR捆绑在一起。目的1将检验PSD95-nNOS蛋白-蛋白的破坏假设 交互作用会通过条件性位置偏爱和药物自身抑制吗啡诱导的奖赏 管理方法。目标2将测试PSD95-nNOS相互作用的中断将 减弱阿片类药物诱发的伏隔核壳体内的多巴胺动力学，这是奖赏的关键成分 巡回赛。破坏蛋白质之间的相互作用曾被认为是药物不可能达到的目标 发展。完成这些高风险、高影响的研究将确定扰乱 PSD95-nNOS接口消除阿片类药物奖励，同时保留治疗效果，绕过不需要的 NMDAR拮抗剂和一氧化氮合酶催化抑制剂的副作用。对我们假设的验证将提供 进行PSD95-nNOS抑制剂的先导优化以进入临床的强有力的理由 对阿片成瘾的研究，填补了未得到满足的治疗需求领域的一个重大空白。

Project Summary Excessive glutamate signaling through N-methyl-D-aspartate receptors (NMDARs) is implicated in altered forms of neuronal plasticity associated with opioid reward and dependence. The present Cutting Edge Basic Research Award proposes to functionally decouple signaling complexes downstream of NMDAR activation to eliminate aberrant NMDAR-dependent nitric oxide signaling and circumvent the development of opioid reward. In the United States, unintentional deaths due to prescription drug overdoses have more than tripled since 1990, more than deaths attributed to cocaine and heroin combined. The increase in unintentional drug overdose death rates has mainly been driven by increased use of opioid analgesics. Inadequate treatment for pain, exacerbated by incomplete analgesic efficacy and narcotic abuse liability, contributes to escalating drug use, resulting in socioeconomic costs estimated at $600 billion annually. Improving the safety, efficacy, side effect profile and abuse liability of opioid analgesics thus remains an urgent medical need. Excessive NMDAR stimulation triggers a signaling cascade involving activation of the enzyme neuronal nitric oxide synthase (nNOS), which catalyzes formation of the signaling molecule nitric oxide (NO), which promotes addiction- related behaviors. Inhibition of aberrant glutamatergic hyperexcitability and inhibition of nNOS reduces addiction-related behaviors in preclinical studies. However, the therapeutic potential of NMDA receptor antagonists and NOS inhibitors are limited by severe side effects. We propose to functionally decouple NMDARs from nNOS signaling to circumvent opioid reward without unwanted side effects of global NMDAR antagonists or nonselective NOS catalytic inhibitors. We propose to accomplish this objective by selectively disrupting the protein-protein interface between nNOS and postsynaptic density 95kDA, a scaffolding protein which tethers nNOS to NMDARs. Aim 1 will test the hypothesis that disruption of PSD95-nNOS protein-protein interactions will suppress morphine-induced reward using conditioned place preference and drug self- administration approaches. Aim 2 will test the hypothesis that disruption of PSD95-nNOS interactions will attenuate opioid-induced dopamine dynamics in the nucleus accumbens shell, a key component of the reward circuit. Disruption of protein-protein interactions was once considered an impossible target for drug development. Completion of these high risk, high impact studies will establish the feasibility of disrupting the PSD95-nNOS interface to eliminate opioid reward, while retaining therapeutic efficacy, bypassing unwanted side effects of both NMDAR antagonists and NOS catalytic inhibitors. Validation of our hypotheses will provide a strong rationale for undertaking lead optimization of PSD95-nNOS inhibitors for advancement toward clinical studies in opioid addiction, filling a major gap in an area of unmet therapeutic need.