Receptors and Second Messengers for Pain and Analgesia

疼痛和镇痛的受体和第二信使

• 批准号: 7908070
• 负责人: JON DAVID LEVINE
• 金额: $ 2.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908070
• 关键词: Absence of pain sensation; Acute; Adrenergic Agents; Analgesics; Anatomy; Chronic; Clinical; Collaborations; Equipment; GTP-Binding Proteins; Head; Knowledge; Morbidity - disease rate; Nociception; Nociceptors; Opioid; Pain; Phosphotransferases; Program Research Project Grants; Regulation; Research; Role; Second Messenger Systems; Signal Pathway; Syndrome; Techniques; Transgenic Model; adrenergic; chronic pain; economic impact; interdisciplinary approach; novel; receptor; second messenger; skills; success

DESCRIPTION (provided by applicant): Chronic pain, a major clinical problem causing significant morbidity and economic impact, is presently treated with limited success, in large part due to inadequate understanding of its underlying mechanisms. The objective of this Program Project grant is to elucidate cellular mechanisms of acute and chronic nociception in the primary afferent nociceptor. Because some of the mechanisms we will investigate appear to be selective for the nociceptor, these studies can potentially identify novel highly selective nociceptor-targeted analgesic therapies. This group of PIs will contribute very complementary arrays of knowledge and skills, conduct formal and informal research collaborations, and share equipment and techniques, especially those related to anatomy and transgenic models of acute and chronic pain. Drs. Jon Levine (Project #1) and Robert Messing (Project #2) will evaluate the contribution of PKCepsilon to nociceptor function. Specifically, Dr. Levine will focus on second messengers in nociceptors upstream of PKCepsilon, and Dr. Messing will determine targets that lie downstream of PKCepsilon. Together, these two projects will provide the first detailed description of this nociceptor-specific second messenger signaling pathway and its function in acute and chronic pain. Dr. Mark von Zastrow (Project #3) will explore the distribution and regulation of opioid (antinociceptive) and beta2- adrenergic (pronociceptive, upstream of PKCepsilon) receptors in nociceptors. He will also analyze the role of G- protein related kinase 2 (GRK2) in setting the sensitivity of the function of these two receptors in nociceptors. Finally, an Anatomy Core headed by Dr. Allan Basbaum, (Core B) will provide high very level support for the large number of anatomical studies in all three projects. This multidisciplinary approach to elucidating the function of nociceptors will significantly increase our understanding of mechanisms underlying pain syndromes and will elucidate key targets for novel therapies for acute and chronic pain.

描述（由申请人提供）：慢性疼痛是一种导致严重发病率和经济影响的主要临床问题，目前治疗效果有限，很大程度上是由于对其根本机制了解不足。该计划项目拨款的目的是阐明初级传入伤害感受器中急性和慢性伤害感受的细胞机制。由于我们将研究的一些机制似乎对伤害感受器具有选择性，因此这些研究有可能确定新型高度选择性的伤害感受器靶向镇痛疗法。这组 PI 将贡献非常互补的知识和技能，开展正式和非正式的研究合作，并共享设备和技术，特别是与急性和慢性疼痛的解剖学和转基因模型相关的设备和技术。博士。 Jon Levine（项目#1）和 Robert Messing（项目#2）将评估 PKCepsilon 对伤害感受器功能的贡献。具体来说，Levine 博士将重点研究 PKCepsilon 上游伤害感受器中的第二信使，Messing 博士将确定 PKCepsilon 下游的目标。这两个项目将共同首次详细描述这种伤害感受器特异性第二信使信号通路及其在急性和慢性疼痛中的功能。 Mark von Zastrow 博士（项目 #3）将探索伤害感受器中阿片类药物（镇痛药）和 β2-肾上腺素能（促痛药，PKCepsilon 上游）受体的分布和调节。他还将分析 G 蛋白相关激酶 2 (GRK2) 在设定伤害感受器中这两种受体功能的敏感性中的作用。最后，由 Allan Basbaum 博士领导的解剖核心（核心 B）将为所有三个项目中的大量解剖研究提供高水平支持。这种阐明伤害感受器功能的多学科方法将显着增加我们对疼痛综合征潜在机制的理解，并将阐明急性和慢性疼痛新疗法的关键靶点。