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: 10158415
• 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/10158415
• 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; addiction; 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。滥用责任是 特别重要。最近阿片类药物滥用的流行已造成重大 医疗、社会和经济问题。其他副作用包括呼吸系统 抑郁症是致命的药物过量的原因，耐受性使治疗变得复杂， 增加副作用以及运动和认知障碍的风险。尽管有这些和 其他不良反应，基于 100 年前发现的化合物的药物 前代表了大多数可用的阿片类药物。以创新的方式 开发止痛药，我们开发了天然脑肽的修饰 从而产生了一种稳定的、MOR选择性的、高效的镇痛剂，并减少了 与吗啡相关的几种副作用。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) 神经胶质细胞 p38/CGRP/P2X7 受体信号传导，以及 e) 两只动物的奖励/滥用潜力 模型-条件性位置偏好（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 该先导化合物（内吗啡类似物 ZH853）在测试中的作用表明： 滥用责任。其中包括依赖性测试（由戒断症状表明） 和厌恶行为），以及在已知增强药物的条件下进行的 CPP 和 SA 测试 寻求和服用（之前使用阿片类药物和压力）。缺乏有价值的财产 ZH853 在这些条件下将增强其不会被滥用的可能性 人类，这对于前瘾君子的疼痛治疗很有用。我们还将 测试 ZH853 可用于阿片类药物维持治疗的可能性 瘾。后者将在 CPP 和 SA 的恢复范例中进行测试 吗啡诱导的效应被扑灭，然后测试 ZH853 减少/防止恢复。我们还将研究一种可能的机制 有助于 ZH853 不同的、更有利的形象：我们已经证明 ZH853 不会产生吗啡在脊髓中显示的神经胶质细胞活化作用，并且 与耐受性相关。我们将评估大脑中的神经胶质细胞激活是否存在差异 奖励系统导致奖励相对缺乏（这与成瘾相关） ZH853 与吗啡相比。研究的成功结果将 支持 ZH853 的概念：1) 即使在条件下也具有较低的滥用可能性 已知会增加吸毒的可能性（之前使用阿片类药物和压力），2) 可能 为先前对阿片类药物成瘾的患者安全地提供有效的疼痛缓解，3) 可以 为阿片类药物成瘾提供维持治疗，并且 4) 在机制上不同于 吗啡由于缺乏神经胶质细胞的激活和奖励中神经胶质神经元的可塑性 系统。加上之前展示的广泛的减少边范围 效应，这些结果将提供证据表明 ZH853 可能是理想的候选者 解决对退伍军人和一般人最重要的两个领域 人群：1）更安全、更有效地缓解疼痛，2）减少阿片类药物滥用。