Cyanobacterial Natural Products to Treat Comorbid Pain and Depression

描述(申请人提供)：这项提案将寻求使用新的天然产品来研究和治疗疼痛、抑郁、焦虑以及疼痛和情感障碍的共病情况。最近的证据表明，慢性疼痛和精神疾病之间存在显著的相互作用。特别是，慢性疼痛(如纤维肌痛、慢性下腰痛、痛性膀胱综合征)似乎在流行病学和生物学上都与严重抑郁障碍(MDD)有关。慢性疼痛患者的MDD或抑郁/焦虑症状的发生率非常高。在这种情况下，这两种不同的疾病实际上相互加强，创造了一个极其危险的病理环境。有趣的是，这种重叠为患者的治疗提供了一种重要的新机制和治疗途径。也就是说，这些常见的机制可能有助于开发出用一种药物对这两种疾病都有效的治疗方法。这一设想将具有双重优势，因为它可以在单一疾病的早期阶段用作预防性治疗，以防止继发性疾病(即疼痛或抑郁)的发展。我们的目标是通过针对5-羟色胺G蛋白偶联受体(GPCRs)的新化合物来测试疼痛和抑郁的常见机制可以用于靶向这些疾病的假设。5-羟色胺是一种大脑神经化学物质，5-羟色胺受体是精神疾病以及最近在慢性疼痛障碍中最常见的靶标之一。然而，大多数使用5-羟色胺靶向药物的研究都使用了最初被筛选为抗抑郁或止痛剂的既定药物，而不是两者兼而有之。我们的目标是在最初的测试中测试我们的化合物是否存在慢性疼痛和抑郁/焦虑，从而提高其成功的可能性。我们将测试提取物、馏分和提纯 来自海洋蓝藻的化合物以前在巴拿马高度生物多样性的水域收集。从海洋环境中发现天然产物是一个相当新的研究领域，但已经在各种疾病领域产生了大量有趣和重要的化合物。主要的研究集中在发现有毒化合物作为抗菌、抗真菌或抗癌药物的用途。然而，这项提案将使用初步筛选抗GPCRs的体内小鼠模型，检查海洋蓝藻提取物调节5-羟色胺GPCRs、治疗疼痛和抑郁的能力。

DESCRIPTION (provided by applicant): This proposal will look to use novel 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 psychiatric illness. In particular, chronic pain (e.g. fibromyalgia, chronic lower back pain, painful bladder syndrome) seems to be linked both epidemiologically and biologically with major depressive disorder (MDD). Rates of MDD or depressive/anxiety symptoms in chronic pain patients are very high. In this situation, the two separate diseases actually potentiate one another to create an acutely dangerous pathological environment. Interestingly, this overlap presents an important new mechanistic and therapeutic avenue for the treatment of patients. That is, these common mechanisms might be useful for the development of 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, however, have used established drugs that were originally screened as either antidepressive OR analgesic agents, not both. We aim to improve the likelihood of success of our compounds by testing them for comorbid chronic pain and depression/anxiety during the initial testing. We will be testing extracts, fractions, and purified compounds from marine cyanobacteria previously collected in the highly biodiverse waters of Panama. The discovery of natural products from the marine environment is a fairly recent field of research but has yielded a large number of interesting and important compounds in a variety of disease areas. 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 marine cyanobacteria for their ability to modulate serotonin GPCRs, to treat pain and depression, using in vivo mouse models following initial screening of the extracts against GPCRs.