Analgesic Signaling in Drosophila

镇痛，即对能够损伤组织的伤害性刺激的伤害性反应的抑制，是一种治疗疼痛的方法。 生物体的适应性行为反应-使它们在生理上适当的环境中感受到较少的疼痛 例如身体创伤或战斗/逃跑反应。传统上，镇痛的研究 脊椎动物模型，其中内源性阿片肽与其同源受体结合以抑制行为 对疼痛刺激的反应。遗传学上易处理的模式生物，如果蝇，最近被用来 探索组织损伤后伤害感受和伤害感受敏化的分子/遗传基础， 还没有被用来剖析保守的镇痛信号。果蝇提供了基因分析的速度 和各种复杂的基因工具，用于分析基因表达和功能，应该证明， 对现有镇痛研究实验范例的有价值的补充。我们在这方面的长期目标 基础研究项目是鉴定和表征果蝇幼虫中的镇痛信号通路。的 我们的初步发现证明了这种途径可能存在，即阿片化合物吗啡是 果蝇幼虫的镇痛药，并且在这一过程中需要保守的G蛋白偶联受体（GPCR）。 热镇痛的生物体。吗啡喂养苍蝇幼虫引起短暂的镇痛，跨越多个 感觉方式（热，冷，触摸，化学），被其他阿片类药物（芬太尼）模仿，部分是纳洛酮 可逆的我们在项目初期的短期目标是确定以下方面所需的气体化学还原的特征： 热镇痛利用我们对哪些组织表达GPCR的了解，我们将确定哪些组织 功能上需要它来镇痛，并评估假定受体的镇痛作用是否延伸到其他受体。 超越热量的感官形态在生化水平上，我们将测试GPCR（它是最清楚的人类） 直系同源物）直接结合吗啡以激活信号传导。在遗传水平上，我们将鉴定内源性肽 配体和探针与先前鉴定的伤害感受基因的遗传相互作用和伤害感受敏化 信号通路在我们的最终目标，我们将探讨吗啡管理（钙变化）的细胞效应 以及已知的吗啡的有害生物副作用、耐受性和便秘的发展 在我们的新模型中也可以观察到。这些目标的成功完成将为我们提供一个全面的蜂窝网络。 和遗传分析镇痛信号在这个新的模型-基本信息，可能产生可测试的 脊椎动物模型中正在进行的工作的假设。展望未来，这种新的镇痛信号模型将 提供了无偏见的基因发现方法的可能性，这些方法应该允许鉴定新的 镇痛所需的保守基因-在某些情况下可能与人类和 值得在脊椎动物模型和临床环境中进一步探索。

Analgesia, the dampening of nociceptive responses to noxious stimuli capable of damaging tissues, is an adaptive behavioral response for organisms- allowing them to feel less pain in physiologically appropriate situations such as physical trauma or the fight/flight response. Analgesia has traditionally been studied in vertebrate models, where endogenous opioid peptides bind to their cognate receptors to dampen behavioral responses to painful stimuli. Genetically tractable model organisms such as Drosophila have recently been used to explore the molecular/genetic bases of nociception and nociceptive sensitization following tissue injury but have not yet been used to dissect conserved analgesia signaling. Drosophila offer both speed of genetic analysis and a variety of sophisticated genetic tools for analyzing gene expression and function that should prove a valuable complement to existing experimental paradigms for the study of analgesia. Our long-term goal in this basic research project is to identify and characterize analgesic signaling pathways in Drosophila larvae. That such pathways are likely to exist is evidenced by our preliminary findings that the opiate compound morphine is analgesic for Drosophila larvae and that a conserved G-protein coupled receptor (GPCR) is required in this organism for thermal analgesia. Morphine feeding to fly larvae causes transient analgesia that spans multiple sensory modalities (heat, cold, touch, chemical), is mimicked by other opiates (fentanyl) and is partially naloxone reversible. Our short-term goals over the initial project period will be to characterize the GPCR required for thermal analgesia. Using our knowledge of which tissues express the GPCR we will determine which tissues functionally require it for analgesia, and assess whether the putative receptor’s analgesic effects extend to other sensory modalities beyond heat. At the biochemical level we will test whether the GPCR (and it’s clearest human ortholog) directly binds morphine to activate signaling. At the genetic level we will identify endogenous peptide ligand(s) and probe genetic interactions with previously identified nociceptive genes and nociceptive sensitization signaling pathways. In our final aim we will probe cellular effects of morphine administration (calcium changes) and whether known deleterious biological side effects of morphine, development of tolerance and constipation are also observed in our new model. Successful completion of these aims will provide a comprehensive cellular and genetic analysis of analgesic signaling in this new model- basic information that is likely to generate testable hypotheses for ongoing work in vertebrate models. Moving forward, this new model of analgesic signaling will provide the possibility of unbiased gene discovery approaches that should allow for identification of novel conserved genes required for analgesia- targets that may in some cases be potentially relevant to human and health and worthy of further exploration in vertebrate models and clinical settings.