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护理，但由于副作用和耐受性和依赖性的发展，仍然是治疗SCD疼痛的次优方法，特别是在持续使用的情况下。因此，镰状病人生活在复发性难以治疗的疼痛中，导致频繁住院和丧失生产力。因此，迫切需要开发无成瘾性和耐受性的有效疗法来治疗SCD中的严重疼痛。我们最近证明，在慢性疼痛动物模型中，痛觉肽受体（NOP）激动剂具有显著的抗痛觉和抗异动作用，其效果与阿片类吗啡在同一模型中的效果相当。我们进一步证明，双功能NOP/阿片激动剂也具有抗异动活性，并且不会产生耐受性，也没有奖励作用。痛觉肽受体NOP及其内源性配体痛觉肽/孤啡肽FQ （nociceptin/orphanin FQ, N/OFQ）广泛分布于大脑和脊髓中参与痛觉反应的区域，是疼痛治疗的靶点。NOP系统还调节阿片效应，如抗痛觉、阿片诱导的耐受性和奖励。因此，从治疗的角度来看，NOP受体激动剂似乎是一种广泛的、有前途的药物策略，可以缓解镰状细胞疼痛，而不存在与阿片类药物治疗相关的副作用，如便秘、耐受性和依赖性。因此，本申请提出概念验证研究，以调查NOP激动剂治疗镰状细胞病相关慢性疼痛的疗效，具体目的如下：目的1：确定一种NOP激动剂和一种双功能NOP激动剂/mu部分激动剂，它们具有合适的药物样特性和脑穿透性，用于疗效研究的评估。目的2：观察NOP激动剂和NOP /mu部分激动剂对镰状小鼠疼痛的镇痛作用。我们将研究其对以下方面的影响：(a)慢性疼痛的强直性痛觉过敏，(b)缺氧/再氧化引起的血管闭塞“危像”引起的急性疼痛，以及(c)炎症和器官病理，以排除nop类镇痛药的不良影响。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，包括皮肤和深层组织痛觉过敏和冷热敏感性的测试，这将为SCD患者临床观察到的不同疼痛特征提供全面的研究。这些研究将有助于将NOP受体激动剂对慢性疼痛的有希望的疗效转化为治疗用途，以扩大缓解SCD疼痛的选择，而不会产生无意的阿片类药物相关副作用。从这个项目中发现的有希望的、有效的NOP激动剂可以进一步开发为治疗SCD疼痛的潜在药物疗法。

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.