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.

伤害感受是一个过程，其中一部分体感神经纤维（称为伤害感受器）检测有害刺激并将该信息传输到脊髓和大脑，最终产生不适或疼痛的感知。伤害感受器面临着检测不同环境和疼痛的复杂任务。物理和化学性质的内源性信号；这些信号包括温度、压力、刺激物、瘙痒剂和经过测试的炎症因子，伤害感受器激活会引起急性疼痛。我们的目标是了解伤害感受器如何检测和整合这些信号以响应来自植物或有毒生物的天然产物。作为破译导致伤害感受和疼痛的细胞和分子机制的非常有价值的工具，著名的例子包括使用天然镇痛药，例如吗啡（来自罂粟）和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）和薄荷醇（来自薄荷叶）来识别检测热和冷的离子通道，事实上，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学治疗的有效或潜在靶标，该提案旨在阐明有助于缓解疼痛的分子、细胞和机制。我们将继续利用天然产物药理学的广阔化学“空间”来识别和表征导致不同伤害感受模式的离子通道和感觉神经元亚型。在最还原论的水平上，我们将使用生物物理、生物化学和药理学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。 TRP 通道家族是天然刺激剂的靶标，在热或化学伤害感受中发挥重要作用。在更综合的水平上，我们将使用分子和药理学探针来表征不同的伤害感受器亚型，并使用小鼠来检查其功能。作为一个这样的例子，我们有兴趣描述一组假定的 Aδ 伤害感受器，并探究它们如何导致机械性疼痛，这些研究将提供重要的信息。开发新型镇痛疗法的机制见解。