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

慢性疼痛相关的丘脑皮质活动对疼痛厌恶的影响

• 批准号: 10053677
• 负责人: Andrew Joseph Crowther
• 金额: $ 6.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053677
• 关键词: Acute; Acute Pain; Affective; Aftercare; Analgesics; Anatomy; Animals; Anterior; Area; Attenuated; Behavior; Behavioral; Biological Markers; Brain; Cerebral cortex; Chronic; Cognition; Cognitive; Complex; Complex Regional Pain Syndromes; Devices; Disinhibition; Emotional; Environment; Functional disorder; Generations; Human; Hyperactivity; Hyperalgesia; Image; Injury; Knowledge; Label; Lesion; Light; Link; Liquid substance; Location; Measures; Mechanics; Mental Depression; Methods; Modality; Modeling; Monitor; Morphine; Mus; Nerve; Neurons; Neuropathy; Nociception; Operant Conditioning; Opioid; Orofacial Pain; Pain; Pain Measurement; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Nervous System; Persistent pain; Physiology; Population; Pre-Clinical Model; Prefrontal Cortex; Process; Property; Prosencephalon; Quality of life; Research Personnel; Rewards; Rodent; Role; Sensory; Spinal cord injury; Stimulus; Testing; Thalamic structure; Therapeutic; Time; United States; Viral; allodynia; aversive conditioning; awake; base; chronic constriction injury; chronic neuropathic pain; chronic pain; chronic pain patient; chronic painful condition; cingulate cortex; cognitive task; comorbidity; conditioning; experience; gabapentin; human model; imaging approach; in vivo; in vivo imaging; injured; innovation; interest; microendoscopy; multisensory; negative affect; nerve injury; novel; optogenetics; orofacial; pain model; pain processing; pain reduction; painful neuropathy; pre-clinical; preclinical study; respiratory; response; sciatic nerve; sciatic nerve injury; spared nerve; transmission process

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.

项目概要 周围神经系统损伤可引起反复疼痛和负面影响合并症，这是一种明确的 慢性疼痛患者的负担。在人类和临床前模型中，神经性疼痛涉及敏化 造成持续疼痛并产生异常性疼痛的外周和中枢回路，其中无害的刺激 现在很痛苦。尽管我们了解损伤过程的大部分解剖学和生理学 从外周到大脑的信息，我们对前脑回路如何产生疼痛感知的了解 而且其情感成分是有限的。我们最近的研究表明，中背侧的传入活动 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。这种调节是 ACC 中的可塑性机制的结果，该机制会增加 MD活动与厌恶行为之间的相关性。这些发现是我们假设的基础，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，我们提出了体内显微内窥镜检查的创新组合 和电路特异性标记，用于测量基线处的 MD-ACC 活性，以响应研究者诱发的刺激 并在操作环境中使用两种神经损伤引起的临床前疼痛模型。我们的具体目标重点 1. 确定 MD-ACC 活性是否专门编码疼痛相关状态，而不是急性伤害感受； 2. 测试抑制 MD-ACC 活性是否选择性减弱慢性疼痛的疼痛厌恶感 状况; 3. 评估镇痛药与 MD-ACC 活性的相互作用是否存在差异（与其相关） 对抗疼痛厌恶的效力。从这些研究中获得的信息将凸显治疗潜力 针对持续疼痛状态下的医学博士（例如，使用新型药物治疗）并阐述我们的知识 周围神经系统损伤后大脑活动何时何地变得异常。