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

作用于μ阿片受体（莫尔）的阿片类药物是治疗 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产生了重大影响， 医疗、社会和经济问题。其他副作用包括呼吸道 抑郁症，致命过量的原因，耐受性，这使治疗复杂化， 增加副作用、运动和认知障碍的风险。尽管有这些和 其他副作用，基于100年前发现的化合物的药物 阿糖胞苷占可用类阿片的大多数。以创新的方式， 为了开发止痛药，我们开发了一种天然脑肽的修饰物， 这导致了一种稳定的、MOR选择性的、高效的镇痛剂， 与吗啡有关的副作用这些包括减少a）呼吸道 抑郁，B）运动协调障碍，c）耐受性和痛觉过敏，d）神经胶质 p38/CGRP/P2 X7受体信号传导，和e）两种动物中的奖励/滥用潜力 模型-条件位置偏好（CPP）和自我管理（SA）测试-， 与人类虐待倾向相关在这个项目中，我们将进一步表征 这种先导化合物，内吗啡肽类似物ZH 853，在试验中的作用表明， 滥用责任这些测试包括依赖性测试（由戒断症状指示 和厌恶行为），和CPP和SA测试在已知的条件下，以提高药物- 寻求和服用（先前使用阿片类药物和压力）。缺乏回报的属性， ZH 853在这些条件下将加强其不会被滥用的可能性， 这将有助于治疗前成瘾者的疼痛。我们还将 测试ZH 853可能用于阿片类药物维持治疗的可能性， 成瘾后者将在恢复范例中进行测试，其中CPP和SA 然后测试ZH 853对吗啡诱导的细胞的抑制作用。 减少/防止恢复。我们还将研究一种机制， 有助于ZH 853的不同，更有利的配置文件：我们已经表明，ZH 853 不产生脊髓中吗啡所示的神经胶质激活， 与宽容有关。我们将评估大脑中不同的胶质细胞激活是否 奖励系统导致相对缺乏奖励（与成瘾相关 与吗啡相比，ZH 853具有更高的潜力。研究的成功结果将 支持ZH 853：1）即使在条件下也具有低滥用责任的概念 已知会增加药物使用的可能性（既往使用阿片类药物和压力），2）可能 安全地为以前对阿片类药物成瘾的患者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，以及4）在机制上不同于 吗啡由于其缺乏激活胶质细胞和胶质-神经元可塑性的奖赏作用 系统与先前展示的广泛的减少侧一起， 这些结果将为ZH 853可能是理想的候选物提供证据 为解决两个领域的最重要的退伍军人和一般 人群：1）更安全和更有效的疼痛缓解和2）减少阿片类药物滥用。

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.