Regulation of Itch Scratching by Spinal GRP Receptors in Primates

描述（由申请人提供）：瘙痒症（痒感）是一种由许多神经系统疾病引起的症状，折磨着大量的人，用各种药理学药物治疗，疗效不同。很少有人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。最近的研究表明，瘙痒的体内药理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。人类和猴子在感知刺激方面有相似的阈值，负责感觉的神经系统在这两个物种中也有本质上的相似之处。因此，利用有意识行为的猴子进行研究来验证动物行为模型并评估潜在止痒药的有效性是很重要的。特别是，先前的研究表明，鞘内注射吗啡诱导的猴子抓挠行为是由中枢mu阿片受体介导的。利用药理学方法，我们打算利用内源性致痒剂（包括内啡肽和胃泌素释放肽）建立其他实验性瘙痒模型，并在更广泛的环境中评估胃泌素释放肽受体（GRPR）拮抗剂作为止痒药的有效性。本项目拟开展的研究将主要建立和验证鞘内给药各种配体引起的猴瘙痒模型，并评估GRPR拮抗剂在这些模型中的潜在治疗效果。在拟议的研究中，抓挠活动将由录像机监测，并由不了解实验条件的观察者量化。合理选择药物对抓痒活性的潜在衰减将在本研究中进行

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.