MOLECULAR MECHANISMS OF THE ITCH SENSATION IN THE SPINAL CORD

描述(申请人提供)：这项建议的长期目标是研究脊椎水平瘙痒感觉的分子机制。虽然急性瘙痒是一种防御机制，但慢性瘙痒或瘙痒是一个严重的临床问题，目前还没有有效的药物可用。脊髓背侧神经元在处理、整合和将瘙痒信息从外周传递到大脑中是必不可少的。然而，脊髓瘙痒感觉的分子机制还不是很清楚。我们最近发现，胃泌素释放肽受体(GRPR)是蛙皮素样肽受体家族的哺乳动物同源物，在脊髓的瘙痒感觉中具有重要的作用。相比之下，痛感不需要GRPR。因此，GRPR是在中枢神经系统中发现的第一个瘙痒特异性分子。最近，我们还发现，第二种哺乳动物蛙皮素样多肽受体神经梅毒素B受体(NMBR)也可能在介导瘙痒感觉中发挥作用。在这项研究中，我们想要研究GRPR和NMBR在瘙痒和疼痛信号传递中的作用。在目标1中，我们将验证NMBR在调节脊髓瘙痒感觉方面的作用的假设，并确定NMBR和GRPR在这方面是否具有多余的功能。药理学和遗传学方法都将被用来检验这一假设。目的2通过对NMBR突变体和NMBR/GRPR双突变小鼠的痛觉行为和药理学研究，确定痛觉是否需要NMBR，以及NMBR和GRPR在疼痛中是否具有多余的功能。目的3验证脊髓吗啡引起的瘙痒依赖于GRPR/NMBR信号通路的假说。在目标4中，我们将通过消融脊髓中的GRPR/NMBR+细胞来研究GRPR/NMBR+细胞在瘙痒感觉中的作用，然后进行行为学实验。拟议的研究不仅应该描述GRPR和NMBR的作用，还应该描述表达这些受体的神经元在脊髓瘙痒感觉中的作用。总之，我们的研究将揭开瘙痒感觉的核心机制，并为设计治疗慢性瘙痒的新治疗策略铺平道路。公共卫生相关性：慢性瘙痒是一个严重的临床健康问题，很难治疗。我们将研究两种哺乳动物蛙皮素相关受体GRPR和NMBR的作用，以及表达这些受体的神经元在脊髓瘙痒感觉中的作用。我们提出的研究将有助于更好地理解瘙痒通路，并为更好地设计治疗慢性瘙痒的策略铺平道路。

Description (provided by applicant): The long-term objective of this proposal is to study the molecular mechanisms that underlie itch sensation at the spinal level. Although acute itch serves as a defense mechanism, chronic itch or pruritus represents a significant clinical problem for which no effective drugs are available. The dorsal spinal cord neurons are essential in processing, integrating and relaying itch information from the periphery to the brain. The molecular mechanisms underlying itch sensation in the spinal cord, however, are not well understood. We have recently shown that gastrin-releasing peptide receptor (GRPR), a mammalian homologue of bombesin-like peptide receptor family, has an important role in mediating itch sensation in the spinal cord. In contrast, GRPR is not required for pain sensation. GRPR thus is the first itch-specific molecule identified in the central nervous system. Recently, we also found that neuromedin B receptor (NMBR), the second mammalian bombesin-like peptide receptor, may also play a role in mediating itch sensation. In this proposal, we would like to study the roles of GRPR and NMBR in the transmission of itch and pain signals. In aim 1, we will test the hypothesis that NMBR has a role in mediating itch sensation in the spinal cord, and determine whether NMBR and GRPR have redundant function in this aspect. Both pharmacological and genetic approaches will be used to test this hypothesis. Aim 2 will determine whether NMBR is required for pain sensation and whether NMBR and GRPR may have redundant functions in pain by examining pain behaviors of NMBR mutant and NMBR/GRPR double mutant mice and by pharmacological studies. Aim 3 will test the hypothesis that spinal morphine-induced pruritus is dependent on the GRPR/NMBR signaling pathways. In aim 4, we will examine the roles of GRPR/NMBR+ cells in itch sensation by ablating GRPR/NMBR+ cells in the spinal cord followed by behavioral experiments. The proposed studies should not only delineate the roles of GRPR and NMBR but also of neurons expressing these receptors in itch sensation in the spinal cord. Together, our studies will unravel the central mechanisms underlying itch sensation and pave the way for designing new therapeutic strategy to treat chronic pruritus. PUBLIC HEALTH RELEVANCE: Chronic itch is a serious clinical health problem which is difficult to treat. We will study the roles of GRPR and NMBR, two mammalian bombesin-related receptors, and neurons expressing these receptors in the itch sensation in the spinal cord. Our proposed studies will lead to a better understanding of the itch pathway and pave the way for better designing the strategy for the treatment of chronic itch.