Ocular Hyperalgesia in Dry Eye

项目摘要 干眼症（DE）是一种多因素疾病，由泪膜不稳定的迹象定义， 眼部刺激和视力模糊的症状。症状缓解是DE患者寻求的主要原因 医疗护理。然而，减少眼部炎症迹象的局部眼部治疗往往失败 控制中重度病例的症状，DE的外周体征不能可靠地预测 疾病严重程度。这些发现表明，中枢神经系统机制在发展中起着关键作用， 在严重的DE病例中维持眼部疼痛;然而，人们对中枢神经系统知之甚少 与症状性DE相关的眼部信号的处理。证据来源于 电生理学、分子和解剖学方法应用于啮齿动物模型中， 眶外腺切除该项目的总体目标是确定以下机制： 持续性泪液减少后三叉神经脑干神经元的神经兴奋性增加， 神经胶质相互作用有助于改变神经处理和增强保护性眼肌反射。 目的1开发了一种定量感觉测试（QST）协议，以表征编码特性， 雄性和雌性大鼠的眼三叉神经脑干神经元。一种新颖的记录和分析方法， 开发用于评估眼轮匝肌上部和下部的斜视样活动， 测量麻醉大鼠的伤害感受行为。目标2确定“前馈”路径 连接三叉神经尾侧和头侧区域有助于DE中的眼痛觉过敏。目标3 确定：a）驱动小胶质细胞激活的感觉信号是否通过上调Toll样和 嘌呤能P2 x受体，B）小胶质细胞的神经活性产物（IL-1β， c）阻断神经元-神经胶质相互作用改变了神经元和神经胶质细胞上的BDNF）及其受体， 假手术组和DE组雄性动物的眼反应神经元和诱发眼睑肌肉反应的特性， 雌性大鼠通过结合神经记录和眼肌活动， 小胶质细胞活化（嘌呤能受体）、炎性小体形成（NLRP 3）和小胶质细胞产物 (IL-1β），该项目将提供新的信息，中枢机制的眼过敏性， 泪液缺乏的动物模型。该项目的长期目标是开发新的方法， 评估中度至重度DE病例的症状，并确定是否靶向神经元受体， 小胶质细胞相互作用具有治疗DE中眼痛觉过敏的潜力。

Project Summary Dry eye disease (DE) is a multifactorial condition defined by signs of tear film instability and symptoms of ocular irritation and blurred vision. Symptom relief is the primary reason DE patients seek medical attention. However, topical eye treatments that reduce the signs of ocular inflammation often fail to manage symptoms in moderate to severe cases and peripheral signs of DE do not reliably predict disease severity. These findings suggest a critical role for CNS mechanisms in the development and maintenance of ocular pain in severe cases of DE; however, little is known about central neural processing of ocular signals that are relevant for symptomatic DE. Converging lines of evidence from electrophysiological, molecular and anatomical approaches are applied in a rodent model for tear deficiency, exorbital gland removal. The overall goals of this project are to determine mechanisms for increased neural excitability of trigeminal brainstem neurons after persistent tear reduction and if neuron- glia interactions contribute to altered neural processing and enhanced protective eye muscle reflexes. Aim 1 develops a quantitative sensory testing (QST) protocol to characterize the encoding properties of ocular trigeminal brainstem neurons in male and female rats. A novel recording and analysis method is developed to assess squint-like activity in upper and lower portions of the orbicularis oculi muscle as a measure of nociceptive behavior in anesthestized rats. Aim 2 determines if a “feed forward” pathway connecting caudal with rostral trigeminal regions contributes to ocular hyperalgesia in DE. Aim 3 determines: a) if sensory signals that drive microglia activation do so by upregulating Toll-like and purinergic P2x receptors, b) the distribution and localization neuroactive products by microglia (IL-1β, BDNF) and their receptors on neurons and glia, and c) blockade of neuron-glia interactions alter the properties of ocular-responsive neurons and evoked eyelid muscle responses in sham and DE male and female rats. By combining neural recording and eye muscle activity with approaches that interfere with microglia activation (purinergic receptors), inflammasome formation (NLRP3) and products of microglia (IL-1β), this project will provide novel information on central mechanisms of ocular hypersensitivity in an animal model for tear deficiency. The long-term goals of this project are to develop new approaches to assess symptoms in moderate to severe cases of DE and to determine if targeting receptors for neuron- microglia interactions has therapeutic potential to manage ocular hyperalgesia in DE.