Regulation of Itch Scratching by Spinal GRP Receptors in Primates

描述(由申请人提供)：瘙痒(瘙痒感觉)是一种症状，源于许多神经系统疾病，困扰着大量的人类，并被各种药理药物治疗，效果参差不齐。几乎没有努力开发有效的瘙痒动物模型，用于临床前评估潜在的止痒药物。最近的研究表明，瘙痒的体内药理学存在明显的物种差异，这可能导致对瘙痒研究的不同结果或解释。人类和猴子具有相似的检测刺激的阈值，两个物种负责感觉的神经系统基本上是相似的。因此，重要的是使用有意识的行为猴子进行研究，以验证动物行为模型，并评估潜在的止痒药物的有效性。特别是，先前的研究已经证明，鞘内注射吗啡诱导的猴子抓挠行为是由中枢u阿片受体介导的。利用药理学方法，我们打算使用内源性促瘙痒药包括内啡肽和胃泌素释放肽来建立其他实验性瘙痒模型，并在更广泛的背景下评估胃泌素释放肽受体(GRPR)拮抗剂在猴子行为中作为止痒药的有效性。本项目建议的研究将主要发展和验证鞘内注射不同配体引起的猴瘙痒模型，并将评估GRPR拮抗剂在这些模型中的潜在治疗效果。在拟议的研究中，划痕活动将由录像机监控，并由对实验条件视而不见的观察者进行量化。将在#年研究合理选择的药物对抓挠活性的潜在减弱作用。 不同的实验瘙痒模型。将彻底调查每种药物的剂量-反应曲线、时间进程和可能的副作用。总体而言，这些研究将开发Vald瘙痒动物模型，提高灵长类动物GRPR的科学知识，并推动针对GRPR的创新疗法的发现，用于治疗人类的瘙痒。

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 t 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 conscious behaving 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 endogenous pruritogenic agents including ¿-endorphin and gastrin-releasing peptide and to evaluate the effectiveness of gastrin-releasing peptide receptor (GRPR) antagonists as antipruritics in a broader context in behaving monkeys. The proposed studies in this project will mainly develop and validate the monkey models of itch elicited by intrathecal administration of various ligands and will assess the potential treatment efficacy of GRPR antagonists in these models. 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 vald animal models of itch, improve scientific knowledge of GRPR in primates, and advance the discovery of innovative therapies targeting the GRPR for the treatment of pruritus in humans.