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

NOP 激动剂治疗镰状细胞病疼痛的镇痛潜力

• 批准号: 8394806
• 负责人: Nurulain T Zaveri
• 金额: $ 25.69万
• 依托单位: ASTRAEA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394806
• 关键词: Absence of pain sensation; Acute; Acute Pain; Adverse effects; African American; Age; Agonist; Analgesics; Animal Model; Biological Assay; Brain; Characteristics; Child; Chronic; Constipation; Cutaneous; Data; Dependence; Development; Dose; Evaluation; Exhibits; Family; Heating; Hemolytic Anemia; Hispanics; Hospitalization; Human; Hyperalgesia; Hypoxia; In Vitro; Inflammation; Investigation; Labor Pain; Laboratories; Life; Ligands; Measures; Modeling; Morphine; Mus; Nociception; Opioid; Opioid Receptor; Organ; Pain; Pain management; Pathology; Patients; Penetration; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma; Process; Quality of life; Recurrence; Reperfusion Injury; Research Personnel; Rewards; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Spinal Cord; System; Testing; Therapeutic; Therapeutic Uses; Tissues; Transgenic Mice; Translations; United States; addiction; base; chronic pain; effective therapy; grasp; improved; in vivo; insight; member; mouse model; nociceptin; nociceptin receptor; nociceptive response; novel; novel strategies; receptor; sickling; small molecule; standard of care; vaso-occlusive pain

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.

描述（由申请人提供）：镰状细胞疾病（SCD）与剧烈疼痛有关，这仍然是治疗的主要挑战。阿片类药物是当前的护理标准，但是由于副作用和耐受性和依赖性的发展，仍然是治疗SCD疼痛的亚最佳方法，尤其是在持续使用时。因此，镰状患者患有经常性治疗的疼痛，导致住院和生产力丧失。因此，迫切需要开发有效的疗法，这些疗法缺乏成瘾和耐受性，以治疗SCD的严重疼痛。我们最近证明，在慢性疼痛的动物模型中，nocceptin受体（NOP）激动剂在同一模型中具有与阿片类吗啡相当的疗效，具有显着的抗伤害性和抗差异效应。我们进一步证明，双功能的NOP/阿片类药物激动剂也具有抗差异活动，并且不会产生宽容，也没有自己的奖励作用。 Nocpeptin受体NOP及其内源性配体Nocptin/Orphanin FQ（N/OFQ）在与伤害性反应有关的区域中广泛分布在大脑和脊髓中，并且是疼痛治疗的靶标。 NOP系统还调节阿片类药物的作用，例如抗吸引力，阿片类药物引起的耐受性和奖励。因此，从治疗的角度来看，NOP受体激动剂似乎是一种广泛的，有前途的药理策略，可减轻镰状细胞疼痛的疼痛，而没有与阿片类药物疗法相关的责任，例如便秘，耐受性和依赖性。因此，该应用提出了证明概念研究研究，以研究NOP激动剂在与镰状细胞疾病相关的慢性疼痛治疗方面的功效，并具有以下具体目的：目标1：确定一种NOP激动剂和一种NOP NOP激动剂/MU部分激动剂，具有合适的药物样和大脑的特征和大脑的特征和大脑的特征和大脑渗透，以评估有效研究。目标2：确定NOP激动剂和NOP激动剂/MU部分激动剂对镰状小鼠的镇痛能力。我们将检查（a）代表慢性疼痛的补强性痛觉过敏的影响，（b）由于缺氧/雷氧施加的血管骨化的“危机”，以及（c）炎症和器官病理，排除了基于NOP基于NOP的镇痛学的不良反应。我们将使用最近在实验室中开发的镰状细胞疾病的相关小鼠模型，并采用几种不同的疼痛度量，包括测试皮肤和深层组织痛觉过敏以及对热和冷的敏感性，这将对SCD患者临床观察到的不同疼痛特征进行全面研究。这些研究将促进NOP受体激动剂在慢性疼痛中的有前途的功效转化为治疗用途，以扩大SCD疼痛缓解的选择，而无需阿片类药物相关的副作用。从该项目中发现的有前途的，有效的NOP激动剂可以作为治疗SCD疼痛的潜在药物治疗。 公共卫生相关性：镰状细胞疾病（SCD）的患者在一生中遭受严重疼痛，这是具有挑战性的治疗。阿片类药物是唯一广泛使用的疗法，但不幸的是与副作用（便秘）和耐受性和成瘾的发展有关。在疼痛模型中，诺西特蛋白受体（NOP）激动剂能够产生阿片类镇痛，而没有阿片类药物相关的副作用，例如耐受性和依赖性。如果他们在SCD的动物模型中表现出效率证明，则正如该项目中提出的那样，他们将提供巨大的治疗优势来治疗无阿片类药物相关的副作用而在SCD中的疼痛。