A non-injurious assay to study mechanisms of transmissio

研究传播机制的非损伤性测定

• 批准号: 7332171
• 负责人: Zenaide Quezado
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7332171
• 关键词: non; injurious; assay; study; mechanisms

Although pain is still the most common reason why patients seek health care, the mechanisms of transmission and perception of pain are not entirely understood. Understanding of the neurophysiologic mechanisms by which noxious and non-noxious stimuli are perceived is imperative for the development of new drugs and techniques to treat pain. Therefore, animal models of pain are necessary to further our understanding of the mechanisms of pain transmission. Currently available models to study transmission of pain use heat, pressure, or chemical stimulation to inflict pain. These models have led to many discoveries in the field but have limitations. Some of the limitations include the fact that heat and pressure can be associated with injury to animals, the stimuli can nonspecifically stimulate several types of nerve fibers (A beta-pressure, A delta-sharp pain, C-slow burning pain), and these stimuli can be associated with habituation learning. In order to study the mechanisms of the transmission of noxious stimuli, we developed a novel and non-injurious nociception assay to preferentially study transmission of noxious stimulus via nerve fibers in a live system. We use a neuro-stimulator that delivers electrical stimuli to the skin at different frequencies and intensities and produces transient discomfort without producing injury. Each of the electrical frequencies used preferentially stimulate a specific type of pain fiber and allows for the measure of vocalization threshold for each type of pain fiber. In the model, we define vocalization as the pain avoiding behavior to the electrical stimulus and use it as the end point to measure current vocalization threshold for each of the pain fibers. Unlike currently used pain models that may produce some tissue-injury in order to induce pain, this assay is non-injurious and preferentially stimulates each type of pain fibers. Therefore it might become a valuable tool for the study of the mechanisms of pain. We completed pilot studies for the development of this assay in mice, developed normative values for the response to each frequency, and have fully developed software application to control the neuro-stimulator, and automated a large portion of the protocol. In addition, we are implementing upgrades to enable completely automated data collection and storage. We are now using the model to study the impact of aging as well as the role of neuronal nitric oxide in the transmission of noxious stimuli in specific nociceptive nerve fibers. We are further developing the model to evaluate pharmacologic interventions with systemic and local analgesics, different strains and species of animals, and different pain models.

尽管疼痛仍然是患者寻求医疗保健的最常见原因，但尚未完全了解传播和疼痛感知的机制。对神经生理机制的理解是，人们认为有害和无毒理的刺激是开发新药物和治疗疼痛技术的必不可少的。因此，必须进行疼痛的动物模型，以进一步了解我们对疼痛传播机制的理解。目前可用的模型研究疼痛传播的热量，压力或化学刺激会导致疼痛。这些模型导致了该领域的许多发现，但有局限性。其中一些局限性包括热和压力可能与动物的损伤有关，刺激可以非特异性刺激几种类型的神经纤维（β-压力，三角洲 - s-Sharp疼痛，c-slow烧伤疼痛），并且这些刺激可以与习惯学习相关。为了研究有害刺激的传播的机制，我们开发了一种新颖且无礼的伤害感受测定法，以优先研究活体系中神经纤维的有害刺激的传播。我们使用一种神经刺激剂，该神经刺激剂以不同的频率和强度向皮肤传递电刺激，并导致瞬时不适而不会产生损伤。每个使用的电气频率都优先刺激特定类型的疼痛纤维，并可以衡量每种类型的疼痛纤维的发声阈值。在模型中，我们将发声定义为避免对电刺激行为的痛苦，并将其用作测量每个疼痛纤维的当前发声阈值的终点。与目前使用的疼痛模型不同，可能会产生某些组织伤害以诱发疼痛，该测定法是无吉利的，并且优先刺激每种类型的疼痛纤维。因此，它可能成为研究疼痛机制的宝贵工具。 我们完成了用于开发小鼠该测定法的试点研究，为每个频率的响应开发了规范值，并已完全开发了软件应用程序以控制神经刺激器，并自动化了该协议的很大一部分。此外，我们正在实施升级，以实现完全自动化的数据收集和存储。现在，我们正在使用该模型来研究衰老的影响以及神经元一氧化氮在特定伤害性神经纤维中有害刺激传播中的作用。我们正在进一步开发该模型，以评估使用全身和局部镇痛药，不同菌株和动物物种以及不同疼痛模型的药理干预措施。