Behavioral Pharmacology of Itch

瘙痒的行为药理学

• 批准号: 8323838
• 负责人: MEI-CHUAN KO
• 金额: $ 33.59万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323838
• 关键词: Advanced Development; Adverse effects; Agonist; Animal Model; Animals; Antihistamines; Antipruritics; Attenuated; Behavior; Behavioral; Behavioral Model; Bombesin; Bombesin Receptor; Clinical; Communities; Development; Disease; Dose; Effectiveness; Endorphins; Esthesia; Experimental Models; Histamine; Human; Innovative Therapy; Knowledge; Mediating; Medical; Modeling; Monitor; Monkeys; Morphine; Mus; Opioid; Opioid Receptor; Patients; Pharmaceutical Preparations; Pharmacology; Play; Population; Primates; Pruritus; Reporting; Research; Rodent; Role; Spinal Cord; Stimulus; Symptoms; System; Testing; Time; attenuation; base; behavioral pharmacology; blind; compare effectiveness; improved; in vivo; kappa opioid receptors; kappa(1) opioid receptor; mu opioid receptors; nervous system disorder; neurotransmission; novel; preclinical evaluation; public health relevance; receptor; relating to nervous system; research and development; response; species difference; success; therapeutic target

DESCRIPTION (provided by applicant): Pruritus (itch sensation) is a symptom derived from many nervous system disorders that afflicts a large population of humans and is treated by a variety of pharmacological agents with variable success. Little effort has been made to develop valid animal models of itch for preclinical evaluation of potential antipruritics. Recent studies illustrate distinct species differences in the in vivo pharmacology of itch, which may contribute to different results or interpretations in itch research. Humans and monkeys have similar thresholds for detecting stimuli and the neural systems responsible for sensations in both species are fundamentally similar. Therefore, it is important to conduct studies using unanesthetized monkeys to validate animal behavioral models and to assess the effectiveness of potential antipruritics. In particular, previous studies have demonstrated that intrathecally administered morphine-induced scratching behavior in monkeys is mediated by central mu opioid receptors. Using pharmacological approaches, we intend to establish other experimental itch models using different pruritogenic agents and to determine the effectiveness of kappa opioid receptor agonists as antipruritics in a broader context in behaving monkeys. The proposed studies in this project will test the central hypothesis that activation of kappa opioid receptors attenuates itch evoked by a variety of pruritogenic agents in primates. In the proposed studies, scratching activity will be monitored by video recorders and quantified by observers blind to experimental conditions. The potential attenuation of scratching activity by rationally selected pharmacological agents will be studied in different experimental itch models. The dose- response curve, time course of each agent, and possible side effects will be thoroughly investigated. Collectively, these studies will develop valid animal models of itch, improve scientific knowledge of itch in primates, and advance the discovery of innovative therapies targeting the kappa opioid receptors for the treatment of pruritus in humans. PUBLIC HEALTH RELEVANCE: Itch/Pruritus is a symptom of many clinical disorders and drug treatments that afflicts a large population of humans. However, little research has been made to improve our understanding of the receptor mechanisms of itch and potential antipruritics. The purpose of this application is to establish more experimental itch models in primates and to determine and compare the effectiveness of different drugs as potential antipruritics in a broader context. If proposed aims are achieved, it will facilitate the development of antipruritics and reduce the medical and financial burdens of itch in a global community.

描述（由申请人提供）：瘙痒（瘙痒感）是一种源自许多神经系统疾病的症状，困扰着大量人群，并通过各种药物治疗，取得了不同的成功。几乎没有努力开发有效的瘙痒动物模型用于潜在止痒剂的临床前评价。最近的研究表明，瘙痒的体内药理学存在明显的物种差异，这可能导致瘙痒研究的不同结果或解释。人类和猴子有相似的阈值来检测刺激，两个物种负责感觉的神经系统基本相似。因此，使用未麻醉的猴子进行研究以验证动物行为模型并评估潜在止痒剂的有效性是重要的。特别是，以前的研究表明，鞘内给药吗啡诱导的抓挠行为的猴子是由中央μ阿片受体介导。使用药理学方法，我们打算建立其他实验瘙痒模型，使用不同的致瘙痒剂，并确定κ阿片受体激动剂作为止痒剂在更广泛的范围内在行为猴子的有效性。本项目中的拟议研究将检验中心假设，即κ阿片受体的激活可减弱灵长类动物中各种致敏剂引起的瘙痒。在拟定研究中，将通过录像机监测抓挠活动，并由对实验条件不知情的观察者进行定量。将在不同的实验性瘙痒模型中研究通过合理选择的药理学试剂对抓挠活性的潜在衰减。将彻底研究每种药物的剂量反应曲线、时间过程以及可能的副作用。总的来说，这些研究将开发有效的瘙痒动物模型，提高灵长类动物瘙痒的科学知识，并推进针对κ阿片受体的创新疗法的发现，用于治疗人类瘙痒症。 公共卫生相关性：瘙痒/瘙痒是许多临床疾病和药物治疗的症状，困扰着大量人群。然而，很少有研究已经提高了我们的理解的受体机制的瘙痒和潜在的止痒。本申请的目的是在灵长类动物中建立更多的实验性瘙痒模型，并在更广泛的背景下确定和比较不同药物作为潜在止痒剂的有效性。如果实现了所提出的目标，它将促进止痒剂的发展，并减少全球社会瘙痒的医疗和经济负担。