Receptors and Second Messengers for Pain and Analgesia

描述（由申请人提供）：慢性疼痛是一个主要的临床问题，导致严重的发病率和经济影响，目前治疗的成功率有限，这在很大程度上是由于对其潜在机制的理解不足。本计画计画补助金的目的是阐明主要传入伤害感受器中急性与慢性伤害感受的细胞机制。由于我们将要研究的一些机制似乎对伤害感受器具有选择性，这些研究可能会发现新的高度选择性的伤害感受器靶向镇痛疗法。这组PI将提供非常互补的知识和技能，进行正式和非正式的研究合作，并分享设备和技术，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。Jon Levine博士（项目#1）和Robert Messing博士（项目#2）将评估PKC β对伤害感受器功能的贡献。具体来说，Levine博士将专注于PKC 3上游伤害感受器中的第二信使，Messing博士将确定PKC 3下游的靶点。这两个项目将共同提供对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的第一个详细描述。Mark von Zastrow博士（项目#3）将探索阿片类（抗伤害性）和β 2-肾上腺素能（原伤害性，PKC β上游）受体在伤害感受器中的分布和调节。他还将分析G蛋白相关激酶2（GRK 2）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著增加我们对疼痛综合征机制的理解，并将阐明急性和慢性疼痛新疗法的关键靶点。

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.