Abuse potential of a novel bifunctional opioid ligand

项目总结/摘要 存在显著未满足的临床需求，即找到用于治疗慢性疼痛的有效镇痛药物， 副作用、耐受性发展和滥用潜力较少。我们发现了一本小说 有效阿片样物质配体（AAH 8），在动物模型中对治疗疼痛非常有效，但不产生 耐受性或依赖性时，管理反复。这种化合物似乎对人类 在动物模型中的作用。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 镇痛药，能显著缓解疼痛，几乎没有产生耐受性或成瘾性的风险。AAH 8具有 对μ和δ阿片样物质受体具有相同的亲和力，但它是μ阿片样物质受体激动剂和δ阿片样物质受体激动剂。 受体拮抗剂，似乎穿过血脑屏障。阻断δ-阿片受体 建议改变μ阿片受体的运输，与脱敏，下调， 宽容虽然认为有效的μ阿片类镇痛药不会有滥用潜力是不寻常的，但我们的研究表明， 初步数据表明，混合功效阿片样物质配体标志着比目前的 阿片类镇痛药，特别是用于治疗慢性疼痛。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，减少与长期疼痛相关的不良后果 治疗。本文的目的是检查AAH 8在慢性疼痛模型、药物自身作用模型和慢性疼痛模型中的作用。 与临床使用的阿片类镇痛剂相比，本发明的药物具有更好的给药效果和不良副作用。总体 假设AAH 8在药物自我给药测定中具有有限的增强作用， 在慢性疼痛测定中的功效。为了完成这项工作，将在慢性疼痛模型中评估AAH 8， 在阿片类药物初治和经验丰富的受试者的药物自我给药试验中， 方面的影响.总的来说，这项研究有可能发现一种药物，将大大改善治疗 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.