Injury-induced nociceptive sensitization in adult D. melanogaster

项目摘要 正常疼痛通过警告我们潜在的组织损伤来促进健康，但异常疼痛会降低质量。 世界各地数百万人的生活。受伤后的疼痛敏感化还可以通过减少再次受伤来促进健康 在康复过程中。某些类型的异常疼痛，包括慢性疼痛，是由疼痛的失调引起的 敏化系统。可用于慢性疼痛的治疗方法不足，部分原因是有害的一面 我们最好的镇痛剂阿片类药物的效果随着时间的延长而变得更加危险。更好的治疗方法 不正常的疼痛是非常需要的。我们建议通过开发新的止痛药靶点 果蝇模型的强大遗传工具包。当果蝇被控制剂量的紫外线伤害时 在紫外线(UV)照射下，动物表现出痛觉超敏，这是伤害性敏感化的表现。这意味着 作为回应，受伤的动物会以回避“跳跃”的形式做出明示的回避行为。 与未受伤的动物相比，热刺激的延迟更小。这种损伤引起了敏感化 之前已经在幼蝇身上使用了范例来证明伤害感受器神经元需要信号 通过骨形态发生蛋白(BMP)途径产生痛觉过敏。中的BMP信令组件 苍蝇与它们的哺乳动物同源物非常相似。然而，对幼蝇的研究仅限于较短的时间。 在幼虫化蛹之前可用，在幼虫组织变态时变得不敏感 才能繁衍出一只成虫。这个项目试图建立类似的方法，可以应用于成年苍蝇，这是 活35天或更长时间，对于研究慢性疼痛等过程来说，这是一个更长的时间窗口。初步 结果表明，受紫外线伤害的成虫，就像幼虫一样，确实对有害刺激变得敏感。我们是 现在准备好规划受伤的成年人变得敏感然后恢复正常所需的时间 敏感性，这样我们就可以测试我用来延长疼痛敏感化的基因的作用，而其他基因可能 缩短过敏期。此外，还将研究性别和年龄在疼痛敏化中的作用。 由于苍蝇和哺乳动物的基因、成分之间的功能高度保守 这些实验确定的可能是治疗异常疼痛的新药的靶点 在人类身上。

Project Summary Normal pain promotes health by warning us of potential tissue damage, but abnormal pain reduces the quality of life for millions around the world. Pain sensitization after injury also promotes health by reducing re-injury during healing. Some types of abnormal pain, including chronic pain, result from dysregulation of the pain sensitization system. Available treatment for chronic pain is inadequate, in part because the deleterious side effects of our best analgesics, the opioids, are made more hazardous by longer use. Better treatments for abnormal pain are badly needed. We propose to reveal novel targets for pain medications by exploiting the powerful genetic toolkit of the Drosophila model. When the fruit fly is injured by a controlled dose of ultraviolet (UV) radiation, the animal exhibits allodynia, a manifestation of nociceptive sensitization. This means that the injured animal will react with a nocifensive avoidance behavior in the form of an avoidance 'jump', in response to a thermal stimulus with a reduced delay, compared with uninjured animals. This injury induced sensitization paradigm has previously been used in larval flies to demonstrate that the nociceptor neuron requires signaling by the Bone Morphogenetic Proteins (BMP) pathway to produce allodynia. BMP signaling components in the fly are very similar to their mammalian orthologs. However, studies on larval flies are limited to the short time available before the larva pupariates, becoming insensitive while metamorphosis reorganizes the larval tissues to produce an adult. This project seeks to establish similar methods that can be applied to adult flies, which live for 35 or more days, a much longer time window for studying processes like chronic pain. Preliminary results indicate that UV-injured adults, like larvae, do indeed become hypersensitive to noxious stimuli. We are now ready to map out the time required for injured adults to become sensitized and then return to normal sensitivity, so that we can test the roles of genes that my serve to prolong pain sensitization, while others may shorten the hypersensitive period. The roles of sex and aging in pain sensitization will also be examined. Because of the high degree of functional conservation between fly and mammalian genes, components identified by these experiments may represent targets for novel medications for the treatment of abnormal pain in humans.