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）：慢性疼痛是导致大量发病率和经济影响的一个主要临床问题，目前的成功率很少，这在很大程度上是由于对其基本机制的理解不足。该计划项目授予的目的是阐明主要传入伤害感受器中急性和慢性伤害感受的细胞机制。由于我们将研究的某些机制对于伤害感受器似乎是有选择性的，因此这些研究可以潜在地识别出新型的高度选择性伤害感受器靶向的镇痛疗法。这组PI将贡献非常互补的知识和技能，进行正式和非正式的研究合作，并共享设备和技术，尤其是与急性和慢性疼痛的解剖结构和转基因模型相关的设备和技术。博士。乔恩·莱文（Jon Levine）（项目＃1）和罗伯特·梅辛（Robert Messing）（项目＃2）将评估PKCEPSILON对Nocceptor功能的贡献。具体来说，莱文博士将重点关注PKCEPSILON上游Nocteptors的第二使者，Messing博士将确定位于PKCepsilon下游的目标。这两个项目将共同提供该伤害感受器特定的第二信使信号通路及其在急性和慢性疼痛中的功能的第一个详细描述。 Mark von Zastrow博士（项目＃3）将探讨病人感伤者中阿片类药物（抗伤害感受）和β2-肾上腺素能（pKcepsilon上游）的分布和调节。他还将分析与G蛋白相关激酶2（GRK2）在树立伤害感受器中这两个受体功能的敏感性中的作用。最后，由Allan Basbaum博士领导的解剖学核心（核心B）将为所有三个项目中的大量解剖学研究提供高水平的支持。这种阐明伤害感受器功能的多学科方法将显着提高我们对疼痛综合症基础机制的理解，并将阐明针对急性和慢性疼痛的新型疗法的关键靶标。