Behavioral Pharmacology of Itch

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，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，我们打算使用不同的致痒剂建立其他实验瘙痒模型，并在更广泛的情况下确定kappa阿片受体激动剂作为止痒剂在行为猴子中的有效性。本项目拟开展的研究将验证kappa阿片受体的激活可减弱灵长类动物由多种致痒剂引起的瘙痒的中心假设。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。我们将在不同的实验瘙痒模型中研究合理选择药物对抓痒活性的潜在衰减。我们将深入研究每种药物的剂量反应曲线、时间过程和可能的副作用。总的来说，这些研究将建立有效的瘙痒动物模型，提高灵长类动物瘙痒的科学知识，并促进发现针对kappa阿片受体治疗人类瘙痒的创新疗法。

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.