Behavioral Pharmacology of Itch

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，这可能有助于在瘙痒研究中产生不同的结果或解释。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，我们打算使用不同的致痒药物建立其他实验性瘙痒模型，并在更广泛的背景下确定kappa阿片受体激动剂在猴子行为中作为止痒药物的有效性。该项目中拟议的研究将检验中心假设，即激活kappa阿片受体可以减轻灵长类动物中各种瘙痒诱导剂引起的瘙痒。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。在不同的实验瘙痒模型中，将研究合理选择的药物对抓挠活性的潜在减弱作用。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，并推动针对kappa阿片受体的创新疗法的发现，用于治疗人类的瘙痒。 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，这些疾病和药物治疗困扰着大量人类。然而，几乎没有研究来提高我们对瘙痒的受体机制和潜在的止痒药物的了解。这一应用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药物的有效性。如果提议的目标得以实现，它将促进止痒药物的开发，并减轻全球社区瘙痒的医疗和经济负担。

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.