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.

作用于单位阿片受体的阿片类药物是最有效的治疗方法。 中度到重度疼痛，但严重的副作用限制了它们的使用。滥用责任是 尤其重要。最近阿片类药物滥用的流行已经产生了重大的 医疗、社会和经济问题。其他副作用包括呼吸系统 抑郁症，致命的过量用药的原因，耐受性，这使治疗和 增加副作用、运动和认知障碍的风险。尽管如此， 其他副作用，基于大约100年前发现的化合物的药物 在现有的阿片类药物中，前一种占大多数。以一种创新的方法 止痛药的开发，我们开发了一种天然脑肽的修饰物 这导致了一种稳定的、更具选择性的、高效的止痛剂，其减少了 与吗啡有关的几种副作用。这些措施包括a)呼吸的减少 抑郁，b)运动协调障碍，c)耐受和痛觉过敏，d)胶质细胞 两种动物的p38/CGRP/P2X7受体信号和e)奖赏/滥用潜能 模型-条件位置偏好(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 这种先导化合物，内吗啡类似物ZH853，在测试中的作用表明 滥用责任。这些测试包括依赖测试(由戒断症状表示 和厌恶行为)，以及在已知条件下进行CPP和SA测试以增强药物- 寻求和服用(以前的阿片类药物使用和压力)。缺乏有价值的资产 在这样的条件下，ZH853将加强其不被滥用的可能性 这将有助于治疗曾经的吸毒者的疼痛。我们还将 检测ZH853用于阿片类药物维持治疗的可能性 上瘾。后者将在CPP和SA的恢复范例中进行测试 然后对ZH853进行检测，以检测ZH853是否 减少/防止复职。我们还将研究一种可能 为ZH853提供不同的、更有利的简介：我们已经证明了ZH853 不会产生吗啡在脊髓中表现出的神经胶质细胞激活， 与耐受性相关。我们将评估大脑中不同的神经胶质激活 奖励制度导致了相对缺乏奖励(这与成瘾有关 ZH853与吗啡进行比较。研究的成功结果将是 支持ZH853：1)即使在条件下也具有较低的滥用责任的概念 已知会增加吸毒的可能性(以前的阿片类药物的使用和压力)，2)可能 安全地为以前依赖阿片类药物的患者提供有效的疼痛缓解，3)可以 为阿片成瘾提供维持治疗，以及4)在机制上与 吗啡在奖赏中缺乏胶质细胞的激活和神经胶质细胞的可塑性 系统。与之前展示的范围广泛的缩小边一起 这些结果将为ZH853可能是一个理想的候选者提供证据 解决对退伍军人和将军最重要的两个领域 人群：1)更安全、更有效的止痛和2)减少阿片类药物滥用。