Receptors and Second Messengers for Pain and Analgesia

描述(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，目前治疗效果有限，很大程度上是由于对其潜在机制的了解不足。本计划项目资助的目的是阐明初级传入伤害性感受器中急性和慢性伤害性感受的细胞机制。由于我们将要研究的一些机制似乎对伤害性感受器具有选择性，这些研究可能会发现新的高度选择性的伤害性感受器靶向止痛疗法。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。乔恩·莱文博士(项目1)和罗伯特·梅辛博士(项目2)将评估PKCepsilon对伤害性感受器功能的贡献。具体地说，莱文博士将专注于PKCepsilon上游伤害性感受器中的第二信使，梅辛博士将确定PKCepsilon下游的靶标。这两个项目将首次详细描述这种伤害性感受器特异的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)将探索阿片类(抗伤害性)和β2-肾上腺素能(原伤害性，PKCepsilon上游)受体在伤害性感受器中的分布和调节。他还将分析G蛋白相关激酶2(GRK2)在确定这两种受体在伤害性感受器中的功能敏感性方面的作用。最后，由艾伦·巴斯鲍姆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非常高水平的支持。这种阐明伤害性感受器功能的多学科方法将显著增加我们对疼痛综合征潜在机制的理解，并将阐明急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.