Pharmacological Studies of NOP Receptors

NOP 受体的药理学研究

• 批准号: 8710778
• 负责人: MEI-CHUAN KO
• 金额: $ 33.77万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8710778
• 关键词: Absence of pain sensation; Acute; Adverse effects; Affect; Affinity; Agonist; Amino Acid Sequence; Analgesics; Behavior; Behavioral; Behavioral Assay; Behavioral Model; Binding; Cardiovascular system; Chronic; Clinic; Communities; Constipation; Development; Dose; Effectiveness; Evaluation; Family; Foundations; Functional disorder; Future; Gastrointestinal Transit; Generations; Health; Healthcare; Human; International; Ligand Binding; Ligands; Measures; Mediating; Medical; Modality; Monkeys; Morphine; Names; Neuropharmacology; Opioid; Opioid Analgesics; Opioid Peptide; Opioid Receptor; Orphan; Pain; Pain management; Patients; Pharmaceutical Preparations; Pharmacology; Physical Dependence; Physiological; Primates; Pruritus; Receptor Activation; Research; Ro 64-6198; Rodent; Safety; Scientist; Sedation procedure; Self Administration; Side; Spinal; Testing; Therapeutic; Time; Ventilatory Depression; Whole Organism; base; biobehavior; clinical application; delta opioid receptor; drug of abuse; gastrointestinal; improved; member; mu opioid receptors; nociceptin; nonhuman primate; novel; preclinical evaluation; receptor; response

DESCRIPTION (provided by applicant): Although mu opioid receptor agonists are the most commonly used opioids for the treatment of moderate to severe pain in the clinic, the side effects of mu opioids such as constipation, respiratory depression, pruritus, abuse liability, and physical dependence limit their value as a medication. Research to identify novel opioids without these side effects is pivotal to advance the health care of humans. Scientists have discovered N/OFQ, a heptadecapeptide that is an endogenous ligand for the novel opioid receptors (now named NOP receptors). The amino acid sequence of the NOP receptor has close homology to each of the classical, well-characterized mu, kappa, delta opioid receptors, but ligands that bind to these classical opioid receptors do not bind to NOP receptors with high affinity. The actions of N/OFQ have much in common with those of opioid peptides at the cellular level. Nevertheless, the behavioral effects of various NOP receptor agonists with different affinity and efficacy have not been systematically studied in primates. The studies proposed in this project will test the hypothesis that functions/behavioral effects of NOP receptors are independent of classical opioid receptors and activation of NOP receptors produces antinociception with fewer side effects and reduced abuse liability in monkeys. In the proposed studies, a variety of physiological and behavioral endpoints will be measured and receptor-selective agonists and antagonists will be used to investigate the functions of NOP receptors. Dose-response curves, time course of each agent, and possible side effects (e.g., scratching, sedation, respiratory depression, cardiovascular changes) will be thoroughly investigated. Proposed studies will help determine whether NOP receptor agonists represent a novel class of opioids that produce analgesia but have fewer side effects in primates. Behavioral effects of NOP receptor agonists will be systematically compared with those of mu opioid analgesics across different, well-established functional/behavioral assays in monkeys. In particular, the therapeutic margin of safety of NOP agonists will be determined in the monkey behavioral models. Our proposed studies, with an emphasis on behavioral effects in the whole organism, are the first attempt to elucidate the functions of NOP receptors in monkeys. These basic studies of behavioral neuropharmacology will establish a valuable translational foundation for understanding of biobehavioral functions of NOP receptors and future research and development of NOP receptor agonists in humans.

描述（由申请人提供）：尽管μ阿片受体激动剂是临床上治疗中度至重度疼痛最常用的阿片类药物，但μ阿片类药物的副作用（如便秘、呼吸抑制、瘙痒、滥用倾向和身体依赖性）限制了其作为药物的价值。确定没有这些副作用的新型阿片类药物的研究对于促进人类的医疗保健至关重要。科学家们发现了N/OFQ，这是一种十七肽，是新型阿片受体（现在称为NOP受体）的内源性配体。NOP受体的氨基酸序列与经典的、充分表征的μ、κ、δ阿片受体中的每一种具有密切的同源性，但是结合这些经典阿片受体的配体不以高亲和力结合NOP受体。N/OFQ的作用在细胞水平上与阿片肽的作用有许多共同之处。然而，各种NOP受体激动剂具有不同的亲和力和功效的行为效应尚未在灵长类动物中进行系统研究。本项目中提出的研究将检验以下假设：NOP受体的功能/行为效应不依赖于经典阿片受体，NOP受体的激活产生抗伤害感受，副作用较少，并降低了猴子的滥用倾向。在拟定的研究中，将测量各种生理和行为终点，并使用受体选择性激动剂和拮抗剂研究NOP受体的功能。剂量-反应曲线、每种药剂的时间过程和可能的副作用（例如，抓挠、镇静、呼吸抑制、心血管变化）将被彻底研究。拟议的研究将有助于确定NOP受体激动剂是否代表一类新型阿片类药物，这些阿片类药物在灵长类动物中产生镇痛作用，但副作用较少。将在猴中通过不同的、完善的功能/行为测定系统地比较NOP受体激动剂与μ阿片类镇痛剂的行为效应。特别地，将在猴行为模型中确定NOP激动剂的治疗安全范围。我们提出的研究，强调在整个生物体的行为影响，是第一次试图阐明猴子的NOP受体的功能。这些行为神经药理学的基础研究将为理解NOP受体的生物行为功能和未来人类NOP受体激动剂的研究和开发奠定有价值的翻译基础。