Natural products as probes of the pain pathway

天然产物作为疼痛通路的探针

基本信息

批准号：
10548116
负责人：
David Julius
金额：
$ 119.52万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548116
关键词：
Acute Acute Pain Acute pain management Afferent Neurons Analgesics Anatomy Binding Biochemical Biophysics Brain Capsaicin Cells Chemicals Chili Pepper Chronic Clinical Complex Detection Development Disease Family Genetic Genus Mentha Goals Hypersensitivity Inflammatory Injury Ion Channel Irritants Mechanics Medication Management Menthol Modality Molecular Morphine Mus Natural Products Nature Nerve Fibers Nociception Nociceptors Opioid Receptor Opium Pain Papaver Pathologic Pathway interactions Persistent pain Pharmaceutical Preparations Pharmacology Physiological Plants Play Population Process Role Salicylic Acids Signal Transduction Spinal Cord Stimulus Syndrome TRP channel Temperature Touch sensation Willow Work chronic pain chronic pain management environmental change environmental disparity imaging modality in vivo imaging insight interest member novel novel therapeutics pharmacologic pressure receptor response somatosensory therapeutic development tool transmission process

项目摘要

Nociception is the process whereby a subset of somatosensory nerve fibers (called nociceptors) detect noxious stimuli and transmit this information to the spinal cord and brain, ultimately producing a percept of discomfort or pain. Nociceptors are faced with the complex task of detecting disparate environmental and endogenous signals of both a physical and chemical nature; these include temperature, pressure, irritants, pruritogens, and inflammatory agents. Consequently, nociceptor activation elicits acute pain as well as injury-evoked pain hypersensitivity and can contribute to so-called ‘maladaptive’ processes underlying persistent pain syndromes. Our goal is to understand how nociceptors detect and integrate these signals in response to changing environmental or physiological conditions. Natural products from plants or venomous creatures have served as tremendously valuable tools for deciphering cellular and molecular mechanisms contributing to nociception and pain. Notable examples include the use of natural analgesics, such as morphine (from the opium poppy) and salicylate (from willow bark) to discover opioid receptors and cyclooxgenases, respectively. Other important examples include the use of natural irritants, such as capsaicin (from chili peppers) and menthol (from mint leaves) to identify ion channels that detect heat and cold, respectively. Indeed, each of these natural product receptors represents a validated or potential target for pharmacological management of acute or chronic pain. This proposal is aimed at elucidating molecules, cells, and mechanisms that contribute to nociception in the context of acute (protective) or pathological (chronic) pain states. We shall continue to exploit the vast chemical ‘space’ of natural product pharmacology to identify and characterize ion channels and sensory neuron subtypes that contribute to distinct nociceptive modalities. At the most reductionist level, we will use biophysical, biochemical, and pharmacological tools to elucidate structural mechanisms underlying ion channel function, including stimulus detection, drug binding, and gating. Here, the main emphasis will be on members of the TRP channel family that are targeted by natural pungent agents and play major roles in thermo- or chemo-nociception. At a more integrative level, we will use molecular and pharmacological probes to characterize distinct nociceptor subtypes, whose functionalities will be examined in mice using genetic, anatomical, and in vivo imaging methods. As one such example, we are interested in characterizing a population of presumptive Aδ nociceptors and asking how they contribute to mechanical pain. Together, these studies will provide important mechanistic insights for the development of novel analgesic therapies.

伤害感受器是体感神经纤维（称为伤害感受器）的子集检测到有害刺激并将这些信息传输到脊髓和大脑，最终产生对不适或疼痛的感知。伤害感受器面临着检测物理和化学性质的不同环境和内源性信号的复杂任务。这些包括温度，压力，刺激性，疗法和炎症剂。因此，伤害感受器的激活会引起急性疼痛以及造成损伤的疼痛超敏反应，并可能导致持续性疼痛综合征的所谓“适应不良”过程。我们的目标是了解伤害感受器如何响应不断变化的环境或身体状况来检测和整合这些信号。来自植物或有毒作品的天然产品已成为破译细胞和分子机制的极有价值的工具，这些机制有助于伤害感受和疼痛。值得注意的例子包括使用天然镇痛药，例如吗啡（来自鸦片）和水杨酸盐（来自柳树树皮）分别发现阿片类药物受体和环氧酶。其他重要的例子包括使用天然刺激物，例如辣椒素（来自辣椒辣椒）和精神病（来自薄荷叶子）分别检测热和冷的离子通道。实际上，这些天然产物受体中的每一个都代表了急性或慢性疼痛的药理治疗的经过验证或潜在的靶标。该建议旨在阐明在急性（保护性）或病理（慢性）疼痛状态下导致伤害感受的分子，细胞和机制。我们将继续探索天然产品药理学的巨大化学“空间”，以识别和表征有助于不同伤害性方式的离子通道和感觉神经元亚型。在最简化的水平上，我们将使用生物物理，生化和药品工具来阐明离子通道功能的结构机制，包括刺激检测，药物结合和门控。在这里，主要重点将是由天然刺激性药物针对的TRP通道家族的成员，并在热或化学感受人中起着重要作用。在更加集成的水平上，我们将使用分子和药物问题来表征不同的伤害感受器亚型，它们将使用遗传，解剖学和体内成像方法在小鼠中检查其功能。作为一个这样的例子，我们有兴趣表征一个占AΔ伤心者的人群，并询问他们如何促进机械疼痛。总之，这些研究将为开发新的镇痛疗法提供重要的机械见解。