CNS Drug Discovery from the Ocean: Cyanobacterial Secondary Metabolites to Treat Comorbid Pain and Depression

项目摘要/摘要 这项提议将使用新的海洋天然产品来研究和治疗疼痛、抑郁、焦虑、 以及痛苦和情感障碍的共病情况。最近的证据表明， 慢性疼痛与抑郁/焦虑之间的相互作用。尤其是慢性疼痛(如纤维肌痛、慢性 腰背痛、膀胱痛综合征)似乎在流行病学和生物学上都与 抑郁/焦虑。在这种情况下，不同的疾病实际上会相互加强，从而创造出一种尖锐的 危险的病理环境。有趣的是，这种重叠提供了一种重要的新机制和 治疗靶点为患者的治疗。也就是说，这些常见机制可能对 开发非阿片类药物治疗，用一种药物对这两种疾病都有疗效。这 方案将具有双重优势，因为它可以在早期阶段用作预防性治疗 预防继发性疾病(即疼痛或抑郁)的单一障碍。我们的目标是 检验这样一种假设，即疼痛和抑郁的常见机制可以用来针对这些 针对5-羟色胺G蛋白偶联受体(GPCRs)的新化合物的疾病。5羟色胺是一种 脑神经化学和5-羟色胺受体是精神疾病和 最近在慢性疼痛障碍方面。大多数使用5-羟色胺靶向制剂的研究都使用了已建立的 神经递质再摄取调节剂，可能以受体特有的方式产生意想不到的影响。那 在一个解剖位置，通过一个受体增加信号可能是抗抑郁的，但 另一种是痛觉过敏。为了了解特定基因的拮抗或协同作用的可能性 受体，我们的目标是同时测试化合物的抗抑郁和止痛性能，以及 在最初的测试中，慢性疼痛和抑郁/焦虑并存的模型。我们将测试萃取物， 级分，以及从高度多样化的水域现有的和新的微生物集合中提纯的化合物 巴拿马和库拉索。从微生物环境中发现天然产物是一个新兴的领域 但研究已经在各种疾病状态下产生了大量有趣和重要的化合物。 主要的研究集中在有毒化合物的发现上，因为它们具有抗菌、抗菌和 真菌，或抗癌药物。然而，这项提案将检查微生物的提取物是否具有精神活性。 化合物及其调节5-羟色胺GPCRs的能力，治疗疼痛和抑郁，使用在体小鼠 遵循GPCRs体外筛选的模型。这项研究的预期结果将是 识别精神活性GPCRs的新配体并增加对共有的 疼痛和抑郁/焦虑的机制。

PROJECT SUMMARY/ABSTRACT This proposal will use novel marine natural products for the study and treatment of pain, depression, anxiety, and comorbid instances of pain and affective disturbances. Recent evidence demonstrates a significant interaction between chronic pain and depression/anxiety. In particular, chronic pain (e.g. fibromyalgia, chronic lower back pain, painful bladder syndrome) seems to be linked both epidemiologically and biologically with depression/anxiety. In this situation, the separate diseases actually potentiate one another to create an acutely dangerous pathological environment. Interestingly, this overlap presents an important new mechanistic and therapeutic target for the treatment of patients. That is, these common mechanisms might be useful for the development of non-opioid treatments that show efficacy against both diseases with a single agent. This scenario would be doubly advantageous in that it could be used as a prophylactic treatment in the early stages of a single disorder to prevent the development of the secondary disease (i.e. pain or depression). We aim to test the hypothesis that the common mechanisms of pain and depression can be used to target these disorders with novel compounds directed at serotonin G-protein coupled receptors (GPCRs). Serotonin is a brain neurochemical and serotonin receptors are one of the most common targets in psychiatric disease and more recently in chronic pain disorders. Most studies using serotonin-targeting agents have used established neurotransmitter re-uptake modulators, which can have unintended effects in a receptor-specific manner. That is, increased signaling through one receptor may be anti-depressant in one anatomical location but hyperalgesic in another. In order to understand the potential for antagonistic or synergistic actions of specific receptors, we aim to test compounds for both anti-depressant and analgesic properties in tandem as well as in a model of comorbid chronic pain and depression/anxiety during the initial testing. We will be testing extracts, fractions, and purified compounds from existing and new microbial collections from the highly diverse waters of Panama and Curaçao. The discovery of natural products from microbial environments is an emerging field of research but has yielded a large number of interesting and important compounds in a variety of disease states. Predominately, studies have focused on the discovery of toxic compounds for their utility as anti-bacterial, anti- fungal, or anti-cancer agents. This proposal, however, will examine extracts from microbes for psychoactive compounds and their ability to modulate serotonin GPCRs, to treat pain and depression, using in vivo mouse models following in vitro screening against GPCRs. The expected outcomes of this research would be identification of novel ligands for psychoactive GPCRs and an increased understanding of the shared mechanisms of pain and depression/anxiety.