The cellular and molecular mechanisms underlying nociception and pain

项目摘要 疼痛的感觉是由强烈的或有害的刺激引起的，例如极端的温度。 或者武力检测有害刺激的能力是生存的基础，因为它提供了一个突出的提醒， 动物的紧迫或持续的危险。在理解如何在 大脑产生疼痛的感觉。值得注意的是，我们对疼痛最有效的药物治疗 目标阿片受体，这是臭名昭著的潜在滥用和作用主要在神经回路 在大脑中。引人注目的是，对于伤害性刺激最初是如何被检测到的， 被称为伤害感受器的初级感觉神经元所控制。伤害感受器通过检测 通过外周器官（如皮肤）中存在的轴突投射的有害刺激。这些信息 然后通过与脊髓神经元的突触连接传递到大脑。为了发展 新的疼痛疗法，有一个根本的需要，以促进我们的细胞和分子的理解， 外周伤害感受器在最近发表的一项研究中，我对数十万人进行了scRNA-seq， 感觉神经元，它确定了多种以前未知的和高度不同的伤害感受器亚型， 神经元，可能具有不同的功能作用。在本提案中，实验室将重点实施我们的 最近开发的分子遗传学工具和方法，从根本上推进我们的理解 疼痛处理的第一步我们将强调一个三层计划，在其中我将彻底审查 (Tier 1）伤害感受器亚型的解剖学/生物物理学特征，（第2层）分子机制 伤害感受器亚型的潜在伤害性刺激检测和（第3层）行为后果 在每种伤害感受器亚型的激活/沉默期间。我们的目标是利用我广泛的先验知识 研究经验，以及关键的初步进展，以开发分子和细胞 了解伤害感受器如何检测伤害性刺激。

PROJECT SUMMARY The perception of pain is caused by intense or damaging noxious stimuli, such as extremes in temperature or force. The ability to detect noxious stimuli is fundamental for survival as it provides a salient reminder to animals of imminent or persistent danger. There have been significant efforts in understanding how the brain generates the perception of pain. Notably, our most efficacious pharmacological treatment for pain target opiate receptors, which are notorious for their potential for abuse and act primarily on neural circuits in the brain. Strikingly, there is a comparatively little known about how noxious stimuli are detected initially by primary sensory neurons known as nociceptors. Nociceptors act as the “first-responders” by detecting noxious stimuli through axonal projections present in peripheral organs, such as the skin. This information is then relayed to the brain via synaptic connections made with spinal cord neurons. In order to develop new pain therapeutics, there is a fundamental need to advance our cellular and molecular understanding of the peripheral nociceptors. In a recently published study, I performed scRNA-seq on hundreds of thousand sensory neurons, which identified multiple previously unknown and highly distinct subtypes of nociceptor neurons, likely with distinct functional roles. In this proposal, the laboratory will focus on implementing our recently developed molecular genetic tools and approaches to fundamentally advance our understanding of the first step in pain-processing. We will highlight a three-tiered plan, in which I will thoroughly examine (Tier 1) the anatomical/biophysical features of nociceptor subtypes, (Tier 2) the molecular mechanisms underlying noxious stimuli detection by nociceptor subtypes and (Tier 3) the behavioral consequences during activating/silencing of each nociceptor subtype. we aim to take advantage of my extensive prior research experience, as well as key preliminary advances, to develop a molecular and cellular understanding of how nociceptors detect noxious stimuli.