Abuse potential of a novel bifunctional opioid ligand

项目摘要/摘要 有一个重大的未得到满足的临床需求，即寻找有效的止痛药来治疗慢性疼痛，这种疼痛 有更少的不良反应，耐受性发展，和滥用的可能性。我们已经确定了一部混合的小说 阿片类药物配基(AAH8)，在动物模型中治疗疼痛非常有效，但不产生 反复给药时的耐受性或依赖性。这种化合物的回报似乎很小。 在动物模型中的影响。这些数据表明，我们的候选化合物可能是最终的阿片类药物。 止痛剂能显著缓解疼痛，几乎不会产生耐受性或成瘾。AAH8有 与Mu和Delta阿片受体亲和力相当，但它是Mu阿片受体激动剂和Delta阿片受体激动剂 受体拮抗剂，似乎能穿过血脑屏障。阻断德尔塔阿片受体 建议改变u阿片受体的运输，与脱敏、下调调节和 宽容。虽然认为有效的阿片类止痛剂不会有滥用潜力的想法是不寻常的，但我们的 初步数据表明，混合疗效的阿片配体标志着比目前的显著改善 阿片类止痛药，尤其用于治疗慢性疼痛。因此，拟议工作的长期目标是 确定慢性疼痛的有效治疗方法，减少与长期相关的不良后果 治疗。本研究的目的是观察AAH8在慢性疼痛、药物自身反应模型中的作用。 与临床使用的阿片类镇痛剂相比，给药和不良反应。最重要的是 假设AAH8在药物自我给药试验中的强化作用有限，并将保留 在慢性疼痛测试中的有效性。为了完成这项工作，AAH8将在慢性疼痛模型和 在阿片类药物幼稚和有经验的受试者中进行药物自我给药测试以确定其增强作用 效果。总体而言，这个项目有可能找到一种可以显著提高治疗效果的药物。 以及通过减少与长期阿片类药物治疗相关的危险来管理慢性疼痛。

Project Summary/Abstract There is a significant unmet clinical need to find effective analgesic drugs for the treatment of chronic pain that have fewer adverse effects, tolerance development, and abuse potential. We have identified a novel mixed efficacy opioid ligand (AAH8) that is highly effective for treating pain in animal models but does not produce tolerance or dependence when administered repeatedly. This compound appears to have minimal rewarding effects in an animal model. These data suggest that our candidate compound may be the ultimate opioid analgesic that produces significant pain relief with little risk of developing tolerance or addiction. AAH8 has equivalent affinity for mu and delta opioid receptors but it is a mu opioid receptor agonist and a delta opioid receptor antagonist and appears to cross the blood brain barrier. Blocking delta-opioid receptors has been proposed to alter the trafficking of mu-opioid receptors as related to desensitization, downregulation, and tolerance. While it is unusual to think that an effective mu-opioid analgesic would not have abuse potential, our preliminary data suggest that the mixed efficacy opioid ligand marks a significant improvement over current opioid analgesics, especially for treating chronic pain. Therefore, the long-term goal of the proposed work is to identify effective treatments for chronic pain with fewer adverse consequences associated with long term treatments. The objective here is to examine the effects of AAH8 in models of chronic pain, drug self- administration, and adverse side effects as compared with clinically used opioid analgesics. The overarching hypothesis is that AAH8 will have limited reinforcing effects in a drug self-administration assays and will retain efficacy in chronic pain assays. To accomplish this work, AAH8 will be evaluated in a chronic pain models and in drug self-administration assays in opioid-naïve and -experienced subjects to determine its reinforcing effects. Overall, this venture has the potential to identify a drug that would dramatically improve the treatment and management of chronic pain by reducing the hazards associated with long term opioid treatment.