Receptors and Second Messengers for Pain and Analgesia

描述（由申请人提供）：慢性疼痛是引起重大发病率和经济影响的主要临床问题，目前治疗成功率有限，很大程度上是由于对其潜在机制的了解不足。本计划的目的是阐明初级传入伤害感受器的急性和慢性伤害感受的细胞机制。因为我们将研究的一些机制似乎对伤害感受器是选择性的，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，特别是与解剖和急性和慢性疼痛的转基因模型有关的设备和技术。Drs。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博士将专注于PKCepsilon上游伤害感受器中的第二信使，Messing博士将确定PKCepsilon下游的靶标。总之，这两个项目将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）将探索阿片（抗痛觉）和β 2-肾上腺素能（前痛觉，PKCepsilon上游）受体在痛觉感受器中的分布和调节。他还将分析G蛋白相关激酶2 （GRK2）在设置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（Core 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.