Pharmacological Studies of NOP Receptors

描述（由申请人提供）：虽然mu阿片受体激动剂是临床上治疗中重度疼痛最常用的阿片类药物，但mu阿片受体激动剂的便秘、呼吸抑制、瘙痒、滥用倾向和身体依赖等副作用限制了其作为药物的价值。鉴别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卫生保健至关重要。科学家们发现了一种名为N/OFQ的七肽，它是新型阿片受体（现在被命名为NOP受体）的内源性配体。NOP受体的氨基酸序列与经典的、具有良好特征的mu、kappa、delta阿片受体具有密切的同源性，但与这些经典阿片受体结合的配体与NOP受体的结合并不具有高亲和力。在细胞水平上，N/OFQ的作用与阿片肽的作用有很多共同之处。然而，各种不同亲和力和功效的NOP受体激动剂对灵长类动物的行为影响尚未得到系统的研究。本项目的研究将验证NOP受体的功能/行为效应独立于经典阿片受体的假设，并且在猴子中激活NOP受体可以产生副作用更少的抗痛觉性，减少滥用倾向。在拟议的研究中，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来研究NOP受体的功能。将彻底调查剂量-反应曲线、每种药物的时间过程和可能的副作用（例如，抓伤、镇静、呼吸抑制、心血管改变）。拟议的研究将有助于确定NOP受体激动剂是否代表一类新的阿片类药物，在灵长类动物中产生镇痛作用，但副作用较小。NOP受体激动剂的行为效应将通过不同的、完善的猴子功能/行为分析系统地与mu阿片镇痛药进行比较。特别是，NOP激动剂的治疗安全边际将在猴子行为模型中确定。我们提出的研究重点是整个生物体的行为效应，这是第一次试图阐明猴子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以及未来人类NOP受体激动剂的研究和开发奠定有价值的转化基础。

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.