Modulating pain through cortical endogenous opioid circuits

通过皮质内源性阿片回路调节疼痛

基本信息

批准号：
10375375
负责人：
Nora McCall
金额：
$ 3.76万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375375
关键词：
Absence of pain sensation Acute Acute Pain Affect Affective Affective Symptoms American Amygdaloid structure Analgesics Anatomy Anterior Area Attention Automobile Driving Behavior Behavioral Behavioral Symptoms Brain Brain region Breathing Cessation of life Clinical Cognition Cognitive Disease Dose Electrophysiology (science)Emotional Emotions Excision Fellowship Glutamates Goals Impaired cognition Impairment Injury Interneurons Label Lesion Life Location Methods Morphine Negative Valence Neurobehavioral Manifestations Neurons Nociception Opioid Opioid Analgesics Opioid Receptor Overdose Pain Pain management Patients Perception Persons Pharmaceutical Preparations Pharmacology Play Process Productivity Quality of life Research Rewards Role Running Sensory Signal Transduction Slice Source Stimulus Synapses System Testing Therapeutic Effect Training Ventilatory Depression addiction cell type chronic pain chronic pain management chronic pain patient cingulate cortex cognitive task cost directed attention effective therapy emotional behavior emotional symptom endogenous opioids genetic predictors goal oriented behavior hippocampal pyramidal neuron improved in vivo mu opioid receptors negative affect nervous system disorder neural circuit neuronal circuitry novel opioid epidemic opioid therapy opioid use optogenetics pain behavior pain perception pain processing pain sensation pain symptom prevent standard of care

Absence of pain sensation Acute Acute Pain Affect Affective Affective Symptoms American Amygdaloid structure Analgesics Anatomy Anterior Area Attention Automobile Driving Behavior Behavioral Behavioral Symptoms Brain Brain region Breathing Cessation of life Clinical Cognition Cognitive Disease Dose Electrophysiology (science)Emotional Emotions Excision Fellowship Glutamates Goals Impaired cognition Impairment Injury Interneurons Label Lesion Life Location Methods Morphine Negative Valence Neurobehavioral Manifestations Neurons Nociception Opioid Opioid Analgesics Opioid Receptor Overdose Pain Pain management Patients Perception Persons Pharmaceutical Preparations Pharmacology Play Process Productivity Quality of life Research Rewards Role Running Sensory Signal Transduction Slice Source Stimulus Synapses System Testing Therapeutic Effect Training Ventilatory Depression addiction cell type chronic pain chronic pain management chronic pain patient cingulate cortex cognitive task cost directed attention effective therapy emotional behavior emotional symptom endogenous opioids genetic predictors goal oriented behavior hippocampal pyramidal neuron improved in vivo mu opioid receptors negative affect nervous system disorder neural circuit neuronal circuitry novel opioid epidemic opioid therapy opioid use optogenetics pain behavior pain perception pain processing pain sensation pain symptom prevent standard of care

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项目摘要

PROJECT SUMMARY Pain is essential to life, serving a vital protective role by directing attention to acute injury or the threatening source of pain. However, unrelenting chronic pain demands unrelenting attention, preventing attendance to other goal-oriented behaviors and reducing quality of life. Chronic pain is characterized by sensory, emotional, and cognitive dysfunction. Opioids, the current standard of care for chronic pain, have a high addictive liability and their misuse can induce respiratory depression and death. This highlights a critical need for improved pain treatment. Interestingly, some chronic pain patients on opioid therapy can perceive pain dissociated from its negative valence, suggesting that alleviation of emotional – or affective – and cognitive symptoms predominantly underlie the analgesic effect of opioids. The research goal of the proposed project is to characterize a novel pain-active subcortical-cortical circuit that selectively contributes to affective-attention pain behaviors, and to determine its overlap with the endogenous mu opioid receptor (µOR) system. The anterior cingulate cortex (ACC), an area known for its involvement in pain perception, emotion, and cognition, plays an executive role in directing attention towards pain. Additionally, opiate analgesic mechanisms resulting from µOR activation are partly localized to the ACC. The ACC receives input from the basolateral amygdala (BLA), which contains a pain- affect valence ensemble required for attending to pain. However, it is unknown if BLA pain-affect valence information is processed in the ACC, or if opioid signaling in the ACC can disrupt this BLA pain-affect input to reduce the perceived negative valence of pain. Aim 1 will determine the necessity and sufficiency of nociception- active BLA (BLAnoci) inputs to ACC in driving pain affective-attention behavior with an in vivo optogenetic approach. In compliment, the synaptic connectivity of BLAnoci inputs to the ACC will be characterized using optogenetic-guided ex vivo slice electrophysiology. Aim 2 will test the necessity and sufficiency of µOR- expressing, nociception-active ACC neurons to reverse chronic pain-impaired affective-attention behavior. The use of opiates to treat the immense emotional and cognitive demand induced by chronic pain facilitates the ongoing Opioid Epidemic. Targeting cortical opioid receptors and nociception-active circuits to selectively lessen the emotional component of pain could be an effective treatment, achieving the long-term objective of this research to identify non-addictive therapies for chronic pain. Completion of this fellowship will achieve the training goals of expanding the experimental expertise of Dr. McCall and establishing her as an expert in the emerging field of pain affect.

项目摘要疼痛对生活至关重要，通过将注意力引起急性伤害或威胁来担任至关重要的角色疼痛来源。但是，持续不屈的慢性疼痛需要毫不留情的关注，以防止参加其他面向目标的行为和降低生活质量。慢性疼痛的特征是感官，情感和认知功能障碍。阿片类药物是当前的慢性疼痛护理标准，具有高的添加责任和他们的小姐可以诱发呼吸抑郁和死亡。这凸显了对疼痛的迫切需求治疗。有趣的是，一些慢性疼痛患者正在接受阿片类药物治疗的患者可以感知疼痛与疼痛分离负面价，表明减轻情绪或情感 - 主要是认知症状阿片类药物的镇痛作用是基础。拟议项目的研究目的是表征小说疼痛活性下皮质皮层回路有选择地有助于情感注意的疼痛行为，并有助于确定其与内源性MU阿片受体（µOR）系统的重叠。前扣带回皮质（ACC）是一个因参与疼痛感，情感和认知而闻名的领域，在将注意力引向疼痛。此外，扩展因激活而引起的镇痛机制是部分位于ACC。 ACC收到来自副杏仁核（BLA）的输入，其中包含疼痛影响疼痛所需的价合奏。但是，尚不清楚bla疼痛影响价是否信息是在ACC中处理的，或者ACC中的阿片类药物信号传导可能会破坏BLA疼痛的输入到减少疼痛的负面价。 AIM 1将确定伤害感受的必要和充分性 - 主动bla（blanoci）输入以驱动疼痛情感注意行为的ACC，并具有体内光遗传学方法。在符合性中，将使用Blanoci输入到ACC的合成连通性。光遗传学的离体切片电生理学。 AIM 2将测试µor-的必要和充分性表达伤害性活性ACC神经元，以逆转慢性疼痛的情感注意行为。使用优化来治疗慢性疼痛引起的巨大情绪和认知需求正在进行的阿片类药物流行。靶向皮质阿片类药物受体和伤害感受激活电路以选择性降低疼痛的情感组成部分可能是一种有效的治疗方法，实现了这一点的长期目标研究以识别慢性疼痛的非成瘾疗法。该奖学金的完成将实现培训麦考尔博士的实验专家的培训目标，并确立她为专家新兴的疼痛领域影响。