A Novel Analgesic with Reduced Side Effects and Abuse Liability Relative to Morphine, With Potential for Opioid Dependence Therapy

一种新型镇痛药，与吗啡相比，副作用和滥用可能性更低，具有治疗阿片类药物依赖的潜力

• 批准号: 10428491
• 负责人: James E Zadina
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428491
• 关键词: Absence of pain sensation; Address; Adverse effects; Affective; Agonist; Analgesics; Animal Model; Area; Basic Science; Behavior; Brain; Chemicals; Chronic; Clinical; Dependence; Development; Dose; Drug Addiction; Drug abuse; Drug usage; Economics; Engineering; Exposure to; Female; General Population; Goals; Human; Hyperalgesia; Impaired cognition; Laboratories; Lead; Maintenance; Maintenance Therapy; Medical; Modification; Morphine; Neuroglia; Neuronal Plasticity; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid replacement therapy; Outcome; Outcome Study; Overdose; Pain; Pain management; Patients; Peptides; Pharmaceutical Preparations; Physical Dependence; Prevention; Process; Property; Rattus; Receptor Signaling; Relapse; Rewards; Risk; Self Administration; Severities; Spinal Cord; Stress; System; Testing; Variant; Ventilatory Depression; Ventral Tegmental Area; Veterans; Withdrawal; Withdrawal Symptom; abuse liability; addiction; addiction liability; analog; base; conditioned place preference; dependence relapse; design; effective therapy; glial activation; innovation; interest; morphine tolerance; motor impairment; mu opioid receptors; mu receptors; novel; novel lead compound; opioid abuse; opioid epidemic; opioid use; p38 Mitogen Activated Protein Kinase; pain reduction; pain relief; side effect

Opioids acting at the mu opioid receptor (MOR) are the most effective therapy for moderate to severe pain, but serious side effects limit their use. Abuse liability is of particular importance. The recent epidemic of opioid abuse has produced major medical, societal and economic problems. Additional side effects include respiratory depression, the cause of fatal overdose, tolerance, which complicates treatment and increases risk of side effects, and motor and cognitive impairment. Despite these and other adverse effects, medications based on compounds discovered around 100 years ago represent a majority of the available opioids. In an innovative approach to the development of pain medications, we developed modifications of a natural brain peptide that resulted in a stable, MOR-selective, highly effective analgesic with a reduction of several side effects relative to morphine. These include reduction in a) respiratory depression, b) impairment of motor coordination, c) tolerance and hyperalgesia, d) glial p38/CGRP/P2X7 receptor signaling, and e) reward/abuse potential in two animal models -conditioned place preference (CPP) and self-administration (SA) tests- that correlate with human abuse liability. In this project we will further characterize the effects of this lead compound, the endomorphin analog ZH853, in tests indicative of abuse liability. These include tests of dependence (indicated by withdrawal symptoms and aversion behaviors), and CPP and SA tests in conditions known to enhance drug- seeking and -taking (previous opioid use and stress). A lack of rewarding properties by ZH853 in these conditions would reinforce the likelihood that it will not be abused in humans and that it would be useful for pain treatment of former addicts. We will also test the possibility that ZH853 could be useful for opioid maintenance therapy for addiction. The latter will be tested in reinstatement paradigms where CPP and SA induced by morphine are extinguished and ZH853 is then tested for reduction/prevention of reinstatement. We will also examine a mechanism likely to contribute to the different, more favorable profile of ZH853: We have shown that ZH853 does not produce the glial activation shown by morphine in the spinal cord and correlated with tolerance. We will assess whether differential glial activation in the brain reward system contributes to the relative lack of reward (that correlates with addiction potential) by ZH853 compared to morphine. Successful outcome of the studies would support the concepts that ZH853: 1) has low abuse liability even under conditions known to enhance the likelihood of drug use (previous opioid use and stress), 2) could safely provide effective pain relief for patients previously addicted to opioids, 3) could provide maintenance therapy for opioid addiction, and 4) is mechanistically distinct from morphine due to its lack of activation of glia and glial-neuron plasticity in the reward system. Together with the previously demonstrated extensive range of reduced side effects, these outcomes would provide evidence that ZH853 could be an ideal candidate for addressing two areas of the highest importance to veterans and the general population: 1) safer and more effective pain relief and 2) reduction of opioid abuse.

作用于MU阿片受体（MOR）的阿片类药物是最有效的治疗方法 中度至重度疼痛，但严重的副作用限制了它们的使用。虐待责任是 特别重要。最近的阿片类药物滥用流行病引起了重大 医疗，社会和经济问题。其他副作用包括呼吸 抑郁症，致命的过量，耐受性，使治疗复杂化和 增加副作用的风险以及运动和认知障碍。尽管如此， 其他不良影响，基于发现大约100年的化合物的药物 以前代表大多数可用的阿片类药物。在一种创新的方法中 开发止痛药，我们开发了自然脑肽的修饰 这导致了一种稳定的，莫斯特尔的，高效的镇痛药，减少了 相对于吗啡的几种副作用。这些包括减少a）呼吸 抑郁症，b）运动协调障碍，c）耐受性和痛觉过敏，d）神经胶质 p38/cgrp/p2x7受体信号，e）两只动物的奖励/滥用潜力 模型 - 条件的位置偏好（CPP）和自我管理（SA）测试 - 与人类虐待责任相关。在这个项目中，我们将进一步描述 该铅化合物的作用，即内啡肽类似物ZH853，在指示的测试中 虐待责任。这些包括依赖性测试（通过戒断症状表示 以及厌恶行为），以及在已知增强药物的条件下进行的CPP和SA测试 寻求和摄取（先前的阿片类药物使用和压力）。缺乏奖励性能 ZH853在这些条件下 人类，这对于以前的成瘾者的疼痛治疗将很有用。我们也会 测试ZH853可能对阿片类药物维持治疗有用的可能性 瘾。后者将在CPP和SA的恢复范式中进行测试 由吗啡诱导的熄灭，然后测试ZH853的 减少/预防恢复原状。我们还将检查一种可能的机制 有助于ZH853的不同，更有利的概况：我们已经证明了ZH853 不会产生吗啡在脊髓中显示的神经胶质激活和 与公差相关。我们将评估大脑中的差异神经胶质激活 奖励系统有助于相对缺乏奖励（与成瘾有关 ZH853与吗啡相比。研究的成功结果将 支持ZH853：1）即使在条件下也承担低责任的概念 已知可以增强吸毒的可能性（以前的阿片类药物使用和压力），2）可以 安全地为先前沉迷于阿片类药物的患者提供有效缓解疼痛，3） 提供阿片类药物成瘾的维持疗法，4）在机械上不同于 吗啡由于缺乏奖励中的神经胶质和神经神经胶质可塑性的激活 系统。加上先前证明的广泛范围的还原范围 效果，这些结果将提供证据表明ZH853可能是理想的候选人 解决对退伍军人和一般最重要的两个领域 人口：1）更安全，更有效的缓解疼痛和2）减少阿片类药物滥用。