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

项目摘要/摘要 阿片类镇痛剂对急慢性疼痛的治疗至关重要，但重要的副作用限制了其安全性 和效用，包括耐受性、便秘、呼吸抑制和滥用责任。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 含α2和α3亚单位的α2/α3GABAA受体上的GABA能信号转导 咪唑二氮类配体MP-III-024具有协同的抗伤害性和抗痛敏作用。 初步数据还表明，MP-III-024/吗啡混合物在行为测试中产生亚加性效应 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MOR和α-2/α-3GABAA，在不增加副作用的情况下增强镇痛效果。我们 假设这种双重药理学方法将导致更有效的抗伤害作用，减少 严重阿片类药物副作用的发展。为了验证这一假设，我们将进行一项全面的临床前研究 MOR-α_2/α_3GABAA双基因药物治疗疼痛、耐受、便秘模型的疗效分析 呼吸抑制和滥用责任。我们将系统测试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，我们会 确定旨在同时靶向MOR和α2/α3GABAA的二价配体是否会产生 具有止痛作用，代表了药物开发的一条新路线。如果成功，这些研究将确定 一种加强阿片类药物镇痛的新方法，依次需要较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.