Analgesic Potential of NOP Agonists to Treat Pain in Sickle Cell Disease

描述（由申请人提供）：镰状细胞病（SCD）与严重疼痛相关，这仍然是治疗的主要挑战。阿片类药物是目前的标准治疗，但由于副作用以及耐受性和依赖性的发展，仍然是治疗SCD疼痛的次优方法，特别是在持续使用时。因此，镰状患者生活在复发性难以治疗的疼痛中，导致频繁住院和生产力损失。因此，迫切需要开发没有成瘾性和耐受性的有效疗法来治疗SCD中的严重疼痛。我们最近已经证明，痛敏素受体（NOP）激动剂在慢性疼痛的动物模型中具有显着的抗伤害性和抗异常性疼痛的作用，与阿片类吗啡的疗效相当，在同一模型中。我们进一步证明了双功能NOP/阿片激动剂也具有抗异常性疼痛活性，并且本身不产生耐受性并且没有奖励作用。伤害感受素受体NOP及其内源性配体伤害感受素/FQ（N/OFQ）广泛分布于脑和脊髓中涉及伤害感受反应的区域，并且是疼痛治疗的靶标。NOP系统还调节阿片样物质的作用，如抗伤害感受、阿片样物质诱导的耐受性和奖赏。因此，从治疗的角度来看，NOP受体激动似乎是一种广泛的、有希望的药理学策略，以提供镰状细胞疼痛的疼痛缓解，而没有与基于阿片样物质的治疗相关的不利因素，如便秘、耐受性和依赖性。因此，本申请提出了研究NOP激动剂在治疗与镰状细胞病相关的慢性疼痛中的功效的概念验证研究，具体目的如下：目的1：鉴定一种NOP激动剂和一种双功能NOP激动剂/mu部分激动剂，其具有合适的药物样特征和脑渗透性，用于功效研究中的评估。目的2：研究NOP激动剂和NOP激动剂/mu部分激动剂对镰状小鼠疼痛的镇痛作用。我们将检查对以下方面的影响：（a）代表慢性疼痛的强直性痛觉过敏，（B）由于缺氧/复氧引发的血管闭塞“危象”引起的急性疼痛，以及（c）炎症和器官病理学，以排除基于NOP的镇痛剂的不良反应。我们将使用我们实验室最近开发的镰状细胞病的相关小鼠模型，并采用几种不同的疼痛测量方法，包括皮肤和深部组织痛觉过敏以及对热和冷的敏感性的测试，这将提供对SCD患者临床观察到的不同疼痛特征的全面调查。这些研究将有助于将NOP受体激动剂在慢性疼痛中的有希望的疗效转化为治疗用途，以扩大SCD疼痛缓解的选择，而不会出现意外的阿片类药物相关副作用。从该项目中鉴定的有前景的有效NOP激动剂可以进一步开发为治疗SCD疼痛的潜在药物疗法。 公共卫生相关性：镰状细胞病（SCD）患者终生遭受严重疼痛，治疗具有挑战性。阿片类药物是唯一广泛使用的治疗方法，但不幸的是与副作用（便秘）以及耐受性和成瘾性的发展有关。孤啡肽受体（NOP）激动剂能够在疼痛模型中产生阿片水平的镇痛，而没有阿片相关的副作用，例如耐受性和依赖性。如果它们在SCD动物模型中证明了疗效，正如本项目所提出的那样，它们将提供巨大的治疗优势来治疗SCD疼痛，而没有阿片类药物相关的副作用。

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is associated with severe pain, which remains a major challenge to treat. Opioids are the current standard of care, but due to side effects and development of tolerance and dependence, remain a sub-optimal approach to treat SCD pain, particularly when used on a continued basis. Sickle patients therefore live with recurrent difficult-to-treat pain, resulting in frequent hospitalization and loss of productivty. Thus there is a critical need to develop effective therapies devoid of addiction and tolerance to treat severe pain in SCD. We have recently demonstrated that nociceptin receptor (NOP) agonists have significant anti-nociceptive and anti-allodynic effects in an animal model of chronic pain, with efficacies comparable to that of the opioid morphine, in the same model. We further demonstrated that bifunctional NOP/opioid agonists also possess anti-allodynic activity, and do not develop tolerance and have no rewarding effects on their own. The nociceptin receptor NOP and its endogenous ligand nociceptin/orphanin FQ (N/OFQ) are widely distributed in the brain and spinal cord in regions involved in nociceptive responses and are a target for pain therapeutics. The NOP system also modulates opioid effects such as anti-nociception, opioid-induced tolerance and reward. Therefore, from a therapeutic standpoint, NOP receptor agonism appears to be a broad, promising pharmacological strategy to provide pain relief in sickle cell pain, without the liabilities associated with opioid- based therapies, such as constipation, tolerance and dependence. This application therefore proposes proof- of-concept studies to investigate the efficacy of NOP agonists in the treatment of chronic pain associated with sickle cell disease, with the following Specific Aims: Aim 1: To identify one NOP agonist and one bifunctional NOP agonist/mu partial agonist, which have suitable drug-like characteristics and brain penetration, for evaluation in efficacy studies. Aim 2: To determine the analgesic ability of NOP agonist and NOP agonist/mu partial agonist on pain in sickle mice. We will examine the effect on, (a) tonic hyperalgesia representing chronic pain, (b) acute pain due to vaso-occlusive "crises" incited by hypoxia/reoxygenation, and (c) inflammation and organ pathology to rule out the adverse effects of NOP-based analgesics. We will use relevant mouse models of sickle cell disease recently developed in our laboratory and employ several different measures of pain including testing for cutaneous and deep tissue hyperalgesia and sensitivity to heat and cold, which will provide comprehensive investigation on different pain characteristics observed clinically in patients with SCD. These studies will facilitate the translation of the promising efficacy of NOP receptor agonists in chronic pain into therapeutic use to expand the options for pain relief in SCD, without inadvertent opioid-related side effects. Promising, efficacious NOP agonists identified from this project can be further developed as potential pharmacotherapy for the treatment of pain in SCD. PUBLIC HEALTH RELEVANCE: Patients with sickle cell disease (SCD) suffer with severe pain throughout life, which is challenging to treat. Opioids are the only therapy widely used but unfortunately are associated with side effects (constipation) and development of tolerance and addiction. Nociceptin receptor (NOP) agonists are able to produce opioid-level analgesia without the opioid-related side effects, such as tolerance and dependence, in models of pain. If they demonstrate proof-of-efficacy in the animal models of SCD, as proposed in this project, they would offer a tremendous therapeutic advantage to treat pain in SCD without opioid-related side effects.