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

项目总结 外周神经系统的损伤会引发反复发作的疼痛和负面情绪共病，一种明确的 慢性疼痛患者的负担。在人类和临床前模型中，神经病理性疼痛涉及敏感化 外周和中枢回路是持续疼痛和产生超感痛觉的基础，在这些回路中，无害的刺激 现在都很痛苦。尽管我们对损伤过程的解剖学和生理学有很多了解 从外周到大脑的信息，我们关于前脑回路如何产生痛觉的知识 它的情感成分是有限的。我们最近的研究表明，内侧背侧的传入活动 丘脑(MD)与前扣带回(ACC)的联系选择性地驱动厌恶条件反射 慢性疼痛状态。这种条件反射是由ACC中的一种可塑性机制引起的，这种机制增加了 MD活动与厌恶行为的相关性。这些发现是我们假设MD- 在慢性疼痛状态下，ACC神经元的活动是厌恶的一个决定因素，它与 伤害性感受。为了挑战我们的假设，我们提出了一种体内显微内窥镜的创新组合 以及电路特异性标记，以测量基线时MD-ACC的活动，以响应调查者诱发的刺激 在手术环境中，使用两种神经损伤诱导的临床前疼痛模型。我们的具体目标和重点 关于1.确定MD-ACC活动是否专门编码疼痛相关状态，而不是急性伤害性感觉； 检测抑制MD-ACC活性是否选择性地减轻慢性疼痛患者的痛觉厌恶 条件；以及3.评估止痛药与MD-ACC活性之间的相互作用是否与其相关 对抗痛觉厌恶的效力。从这些研究中获得的信息将突出治疗潜力。 以处于持续疼痛状态的MD为目标(例如，使用新的药物疗法)，并阐述我们的知识 外周神经系统损伤后大脑活动何时何地发生异常。

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.