Injury-induced nociceptive sensitization in adult D. melanogaster

成年黑腹果蝇损伤引起的伤害性敏化

• 批准号: 10586054
• 负责人: GEOFFREY GANTER
• 金额: $ 7.1万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2023-07-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10586054
• 关键词: Abdomen; Address; Adult; Affect; Age; Aging; Analgesics; Anesthesia procedures; Animals; Behavioral; Biochemical; Biological Assay; Biological Metamorphosis; Biological Models; Bone Morphogenetic Proteins; Candidate Disease Gene; Chronic; Dose; Drosophila genus; Emotional; Epidemic; Exhibits; Exposure to; Future; Genes; Genetic; Genetic Models; Genome; Goals; Health Promotion; Human; Hypersensitivity; Injury; Intractable Pain; Investigation; Knowledge; Larva; Lasers; Lateral; Life; Longevity; Mammals; Maps; Measures; Mechanics; Mediating; Methods; Modeling; Molecular; Morphology; Neurons; Nociception; Nociceptors; Opiate Addiction; Opioid; Orthologous Gene; Pain; Pain Research; Pain management; Pathway interactions; Pharmaceutical Preparations; Population; Process; Protocols documentation; Quality of life; Reaction; Recovery; Resolution; Response Latencies; Rodent; Role; Severities; Sex Differences; Signal Transduction; Signaling Protein; Stimulus; System; Testing; Time; Tissues; Translating; Translations; UV injury; Ultraviolet Rays; Vacuum; addiction liability; age effect; allodynia; avoidance behavior; chronic pain; chronic pain management; economic impact; experimental study; fly; gene conservation; gene discovery; healing; health warning; human disease; injured; innovation; mature animal; neurophysiology; new therapeutic target; novel; pain model; pain reduction; peripheral pain; power analysis; response; restraint; sex; side effect; young adult

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.

项目摘要 正常疼痛通过警告我们潜在的组织损害来促进健康，但异常疼痛降低了质量 全世界数百万人的生活。受伤后的疼痛敏化还可以通过减少伤害来促进健康 在康复期间。疼痛失调引起的某些类型的异常疼痛，包括慢性疼痛 致敏系统。可用的慢性疼痛治疗不足，部分原因是有害的一面 我们最好的镇痛药的影响，阿片类药物，通过更长的使用使危险更大。更好的治疗方法 急需异常的疼痛。我们建议通过利用止痛药的新目标 果蝇模型的强大遗传工具包。当果蝇被控制剂量的紫外线受伤时 （紫外线）辐射，动物表现出异肌，是伤害感受敏化的表现。这意味着 受伤的动物会以避免“跳跃”的形式以一种避免的避免行为做出反应 与未受伤的动物相比，延迟减少的热刺激。这种伤害引起的敏化 以前已在幼虫蝇中使用范式来证明伤害感受器神经元需要信号传导 通过骨形态发生蛋白（BMP）途径产生异常性疾病。 BMP信号传导组件 苍蝇与他们的哺乳动物直系同源物非常相似。但是，对幼虫蝇的研究仅限于短时 在幼虫pupariates之前可用，变态不敏感，重新组织幼虫组织 生产成人。该项目旨在建立可以应用于成年蝇的类似方法， 活35天或更长时间，这是一个更长的时间来研究诸如慢性疼痛之类的过程。初步的 结果表明，像幼虫一样，受紫外线受伤的成年人确实对有害刺激变得非常敏感。我们是 现在准备绘制受伤成年人变得敏感所需的时间，然后恢复正常 敏感性，以便我们可以测试我用来延长疼痛敏感的基因的作用，而其他人可能 缩短了高度敏感的时期。还将检查性别和衰老在疼痛敏化中的作用。 由于苍蝇和哺乳动物基因之间的功能保护高度，因此成分 通过这些实验确定的可能代表用于治疗异常疼痛的新药物的靶标 在人类中。