Molecular Mechanisms of the Itch Sensation in the Spinal Cord

描述（由申请人提供）：本提案的长期目标是研究脊柱水平瘙痒感觉的分子机制。虽然急性瘙痒作为一种防御机制，慢性瘙痒或瘙痒是一个重要的临床问题，没有有效的药物可用。脊髓背侧神经元在处理、整合和传递来自外周的瘙痒信息到大脑中是必不可少的。然而，脊髓中瘙痒感觉的分子机制尚不清楚。我们最近发现胃泌素释放肽受体（GRPR）在介导脊髓瘙痒感觉中起重要作用，GRPR是哺乳动物的bombesin样肽受体家族的同系物。相比之下，GRPR并不是痛觉所必需的。因此，GRPR是第一个在中枢神经系统中发现的瘙痒特异性分子。最近，我们还发现第二种哺乳动物炸弹素样肽受体神经介质B受体（neuromedin B receptor， NMBR）也可能在介导瘙痒感觉中发挥作用。在本提案中，我们想研究GRPR和NMBR在瘙痒和疼痛信号传递中的作用。在aim 1中，我们将检验NMBR在脊髓中介导瘙痒感觉的假设，并确定NMBR和GRPR在这方面是否具有冗余功能。药理学和遗传学方法都将用于验证这一假设。Aim 2将通过检测NMBR突变体和NMBR/GRPR双突变体小鼠的疼痛行为以及药理学研究来确定NMBR是否为疼痛感觉所必需，以及NMBR和GRPR是否在疼痛中具有冗余功能。目的3将验证脊髓吗啡引起的瘙痒依赖于GRPR/NMBR信号通路的假设。在目标4中，我们将通过消融脊髓中的GRPR/NMBR+细胞，然后进行行为实验，研究GRPR/NMBR+细胞在瘙痒感觉中的作用。我们的研究不仅应该描述GRPR和NMBR在脊髓瘙痒感觉中的作用，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，我们的研究将揭示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。

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.