Combination drug therapy to treat pain with minimal or no abuse potential and side-effects

项目总结/摘要 阿片类镇痛药对于急性和慢性疼痛管理至关重要，但重要的副作用限制了其安全性 和效用，包括耐受性、便秘、呼吸抑制和滥用倾向。我们已经确定 与阿片类镇痛剂吗啡同时激活μ-阿片受体（MORs），并增强 在含有α2和α3亚基的GABAA（α2/α3GABAA）受体上的GABA能信号传导， 咪唑二氮杂配体MP-III-024产生协同的抗伤害感受和抗痛觉过敏作用。 初步数据还表明，MP-III-024/吗啡混合物在行为测试中产生亚累加效应 对吗啡副作用敏感，支持进一步研究双重药理学方法， 同时靶向莫尔和α2/α 3 GABAA，以增强镇痛效果而不增加副作用。我们 假设这种双重药理学方法将导致更有效抗伤害感受， 严重的阿片类药物副作用的发展。为了验证这一假设，我们将进行全面的临床前研究。 分析双重莫尔-α2/α 3 GABAA药物治疗在疼痛、耐受、便秘、 呼吸抑制和虐待倾向我们将系统地检测κ-阿片受体或δ-阿片受体 受体也有助于MP-III-024/吗啡混合物的抗伤害感受作用。最后我们将 确定设计用于同时靶向莫尔和α2/α 3 GABAA的二价配体是否会产生 镇痛作用，并代表了一种新的药物开发线。如果成功，这些研究将确定 一种增强阿片类镇痛的新方法，需要更低的阿片类药物必要剂量， 减少危险副作用或阿片类药物依赖和成瘾发展的可能性。

PROJECT SUMMARY/ABSTRACT Opioid analgesics are critical for acute and chronic pain management, but important side effects limit their safety and utility, including tolerance, constipation, respiratory depression, and abuse liability. We have determined that simultaneous activation of µ-opioid receptors (MORs), with the opioid analgesic morphine, and enhancement of GABAergic signaling at α2 and α3 subunit-containing GABAA (α2/α3GABAA) receptors, with the novel imidazodiazepine ligand MP-III-024, produces synergistic antinociceptive and anti-hyperalgesic effects. Preliminary data also indicate that MP-III-024/morphine mixes produce sub-additive effects in behavioral tests sensitive to morphine side effects, supporting further investigation of a dual pharmacological approach that simultaneously targets MOR and α2/α3GABAA to enhance analgesic effects without increasing side effects. We hypothesize that this dual pharmacology approach will result in more effective antinociception with reduced development of critical opioid side effects. To test this hypothesis, we will perform a comprehensive preclinical analysis of the effects of dual MOR-α2/α3GABAA pharmacotherapy in models of pain, tolerance, constipation, respiratory depression, and abuse liability. We will systematically test whether κ-opioid receptors or δ-opioid receptors also contribute to the antinociceptive effects of MP-III-024/morphine mixtures. Finally, we will determine whether bivalent ligands designed to simultaneously target MOR and α2/α3GABAA will produce analgesic effects and represent a new line of medication development. If successful, these studies would identify a new method to enhance opioid analgesia, requiring lower necessary doses of opioid medications, in turn reducing the likelihood of dangerous side effects or the development of opioid dependence and addiction.