GPR171 As a Novel Target to Treat Neuropathic Pain

项目摘要 数百万慢性疼痛患者缺乏足够的治疗方法来治疗他们的疼痛。孤儿g蛋白 偶联受体可能是一种新的途径，以研究治疗疼痛和各种 其他健康问题。一个有趣的候选者是GPR 171，最近被发现是 受体的高度丰富的神经肽，比格伦。这项研究的目的是 是研究这个系统的神经回路，BigLEN-GPR 171，以及它减轻 慢性疼痛我们的初步数据显示GPR 171激动剂具有抗伤害感受特性， 慢性疼痛此外，神经病理性疼痛下调GPR 171的表达在一个关键的时间点内， 大脑区域，导水管周围灰质，参与疼痛调节。我们的假设是 导水管周围灰质内的GPR 171调节神经性疼痛。为了验证这个假设，我们 将使用分子和行为药理学研究GPR 171激动剂， 化学疗法引起的神经性疼痛，并破译哪些大脑区域介导这些 应答目的1将确定用GPR 171激动剂长期治疗的有效性 治疗慢性神经性疼痛GPR 171表达和信号转导在细胞内的改变 慢性疼痛后的下行疼痛回路将在目标2a中使用分子生物学方法进行研究。 技术.目标2b将使用病毒敲除和GPR 171化合物的局部施用， 确定导水管周围灰质在缓解神经病理性疼痛中的作用。总体而言，这 创新研究具有重要的疼痛治疗意义，因为它将提高我们的 了解这种新的神经肽系统的生理功能。

PROJECT SUMMARY Millions of chronic pain patients lack adequate therapeutics to treat their pain. Orphan G-protein coupled receptors could be a new avenue to investigate for the treatment of pain and a variety of other health concerns. One interesting candidate is GPR171 that recently was found to be the receptor of the highly abundant neuropeptide, BigLEN. The purpose of this proposed research is to investigate the neural circuitry of this system, BigLEN-GPR171, and its ability to alleviate chronic pain. Our preliminary data show that a GPR171 agonist has antinociceptive properties in chronic pain. In addition, neuropathic pain downregulates GPR171 expression within a key brain region, periaqueductal gray, that is involved in pain modulation. Our hypothesis is that GPR171 within the periaqueductal gray regulates neuropathic pain. To test this hypothesis, we will use molecular and behavioral pharmacology to investigate a GPR171 agonist on chemotherapy-induced neuropathic pain and decipher which brain areas are mediating these responses. Aim 1 will determine the effectiveness of long-term treatment with a GPR171 agonist on treating chronic neuropathic pain. Alterations in GPR171 expression and signaling within the descending pain circuit following chronic pain will be investigated in Aim 2a by using molecular techniques. Aim 2b will use viral knockdown and local administration of GPR171 compounds to determine the role of the periaqueductal gray in relieving neuropathic pain. Overall, this innovative research has important pain therapeutic implications, as it will enhance our understanding of the physiological functions of this novel neuropeptide system.