The contribution of chronic pain-associated thalamocortical activity to pain aversiveness

项目摘要 周围神经系统损伤可引起复发性疼痛和负面情绪共病， 慢性疼痛患者的负担。在人类和临床前模型中，神经性疼痛涉及致敏作用， 周围和中枢回路的神经系统，这些神经系统是持续疼痛的基础，并产生异常性疼痛， 现在很痛苦。虽然我们对损伤过程的解剖学和生理学都很了解， 从外围到大脑的信息，我们对前脑回路如何产生疼痛感受的知识， 情感成分有限。我们最近的研究表明，传入活动内的中背 丘脑（MD）与前扣带皮层（ACC）的连接选择性地驱动厌恶性条件反射， 慢性疼痛状态这种条件反射是由前扣带回中的可塑性机制引起的， MD活动与厌恶行为之间的相关性。这些发现是我们假设MD- 在慢性疼痛状态下，ACC神经元活动是厌恶的决定因素，并且它与 伤害感受为了挑战我们的假设，我们提出了一个创新的组合，在体内显微内窥镜 和回路特异性标记，以测量基线时MD-ACC活性，以响应刺激器诱发的刺激 在操作环境中，使用两种神经损伤诱导的临床前疼痛模型。我们的具体目标是 一号线。确定MD-ACC活动是否特异性编码疼痛相关状态，而不是急性伤害感受; 2. 测试MD-ACC活性的抑制是否选择性地减弱慢性疼痛中的疼痛厌恶 条件; 3。评估镇痛剂是否与MD-ACC活性有差异地相互作用， 对疼痛厌恶的效力。从这些研究中获得的信息将突出治疗潜力 以MD为目标（例如，与新的药物治疗）在持续的疼痛状态，并阐述我们的知识 在周围神经系统受伤后，大脑活动在何时何地变得异常。

PROJECT SUMMARY Injury to the peripheral nervous system can provoke recurring pain and negative affect comorbidity, an explicit burden of chronic pain patients. In humans and preclinical models, neuropathic pain involves the sensitization of peripheral and central circuits that underlie ongoing pain and produce allodynia, in which innocuous stimuli are now painful. Although we understand much of the anatomy and physiology of the processing of injury information from the periphery to the brain, our knowledge of how forebrain circuits generate the pain percept and its affective component is limited. Our recent studies indicate that afferent activity within the mediodorsal thalamus (MD) connection to the anterior cingulate cortex (ACC) selectively drives aversive conditioning in chronic pain states. The conditioning results from a plasticity mechanism in the ACC, one that increases the correlation between MD activity and aversive behavior. These findings are the basis of our hypothesis that MD- ACC neuronal activity, in chronic pain states, is a determinant of aversiveness, and that it is separate from nociception. To challenge our hypothesis, we propose an innovative combination of in vivo microendoscopy and circuit-specific labeling to measure MD-ACC activity at baseline, in response to investigator-evoked stimuli and in an operant environment, using two nerve-injury induced preclinical pain models. Our specific aims focus on 1. Determining if MD-ACC activity specifically encodes pain-related states, rather than acute nociception; 2. Testing whether inhibition of MD-ACC activity attenuates pain aversiveness selectively in chronic pain conditions; and 3. Assessing if analgesics interact differentially with MD-ACC activity in connection with their potency against pain aversiveness. Information gained from these studies will highlight the therapeutic potential of targeting the MD (e.g., with novel pharmacotherapeutics) in ongoing pain states and elaborate our knowledge of when and where brain activity becomes abnormal after an injury to the peripheral nervous system.