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

联合药物疗法治疗疼痛，且滥用可能性和副作用极小或没有

• 批准号: 10585611
• 负责人: Bradford D Fischer
• 金额: $ 38.9万
• 依托单位: ROWAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585611
• 关键词: Absence of pain sensation; Acute pain management; Affect; Affinity; Agonist; Amides; Analgesics; Base Ratios; Behavioral; Binding; Biological Assay; Carbon; Charcoal; Chronic; Clinical; Combination Drug Therapy; Constipation; Coupling; Dangerousness; Data; Development; Disease; Dose; Drug Combinations; Female; Fentanyl; Food; In Vitro; Investigation; Length; Ligands; Measures; Mediating; Mental Depression; Methods; Modeling; Morphine; Mus; Nociception; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Oxycodone; Pain; Pain management; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Plethysmography; Risk; Route; Safety; Signal Transduction; System; Testing; Therapeutic; Variant; Ventilatory Depression; abuse liability; addiction; antagonist; antinociception; behavior test; chronic pain management; conditioned place preference; connective tissue-activating peptide; delta opioid receptor; design; dorsal horn; efficacy evaluation; experimental study; gamma-Aminobutyric Acid; improved; kappa opioid receptors; male; novel; novel drug class; opioid epidemic; opioid use; pain model; pain relief; pharmacologic; pharmacophore; positive allosteric modulator; pre-clinical; prescription opioid; radioligand; receptor; scaffold; side effect; spinal pathway; synergism; transmission process; treatment strategy

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.

项目概要/摘要 阿片类镇痛药对于急性和慢性疼痛治疗至关重要，但重要的副作用限制了其安全性 和效用，包括耐受性、便秘、呼吸抑制和滥用倾向。 与阿片类止痛药吗啡同时激活 µ-阿片受体 (MOR)，并增强 含 α2 和 α3 亚基的 GABAA (α2/α3GABAA) 受体的 GABA 信号传导，具有新颖的 咪唑并二氮杂卓配体 MP-III-024，产生协同抗伤害和抗痛觉过敏作用。 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α2/α3GABAA以增强镇痛效果而不增加副作用。 研究人员认为，这种双重药理学方法将产生更有效的镇痛作用，同时减少 为了检验这一假设，我们将进行临床前研究。 分析 MOR-α2/α3GABAA 双重药物疗法对疼痛、耐受性、便秘、 我们将系统地测试 κ-阿片受体或 δ-阿片受体。 受体也有助于 MP-III-024/吗啡混合物的镇痛作用。 确定设计用于同时靶向 MOR 和 α2/α3GABAA 的二价配体是否会产生 如果成功，这些研究将确定镇痛作用并代表新的药物开发路线。 一种增强阿片类药物镇痛的新方法，从而需要降低阿片类药物的必要剂量 减少危险副作用或阿片类药物依赖和成瘾的可能性。