Natural products as probes of the pain pathway

伤害性感觉是一组躯体感觉神经纤维(称为伤害性感受器)检测伤害性刺激并将该信息传递到脊髓和大脑，最终产生不适或疼痛的过程。伤害性感受器面临着一项复杂的任务，即检测不同的环境信号和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、瘙痒和炎症介质。因此，伤害性感受器的激活会引起急性疼痛和损伤诱发的疼痛超敏反应，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性感受器如何检测和整合这些信号，以响应不断变化的环境或生理条件。来自植物或有毒生物的天然产物已成为破译导致伤害和疼痛的细胞和分子机制的极有价值的工具。值得注意的例子包括使用天然止痛剂，如吗啡(从罂粟中提取)和水杨酸盐(从柳树皮中提取)来分别发现阿片受体和环氧合酶。其他重要的例子包括使用天然刺激物，如辣椒素(来自辣椒)和薄荷醇(来自薄荷叶)，以识别分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着急性或慢性疼痛的药物治疗的有效或潜在靶点。这一建议旨在阐明在急性(保护性)或病理性(慢性)疼痛状态下，促进伤害性感受的分子、细胞和机制。我们将继续开发天然产物药理学的广阔化学“空间”，以识别和表征离子通道和感觉神经元亚型，这些亚型有助于不同的伤害性感受方式。在最还原的水平上，我们将使用生物物理、生化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。在这里，主要的重点将放在Trp通道家族的成员上，它们是天然刺激性物质的靶标，在热或化学伤害性感受中发挥重要作用。在更综合的层面上，我们将使用分子和药理学探针来表征不同的伤害性感受器亚型，其功能将在小鼠身上使用遗传学、解剖学和活体成像方法进行检测。作为一个这样的例子，我们感兴趣的是描述一组推定的Aδ伤害性感受器，并询问它们如何导致机械性疼痛。总之，这些研究将为新的止痛疗法的发展提供重要的机制见解。

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.