Modulating pain through cortical endogenous opioid circuits

项目总结 疼痛对生命是必不可少的，它通过引导人们对急性损伤或威胁的关注来发挥至关重要的保护作用。 痛苦之源。然而，持续的慢性疼痛需要持续的关注，阻止对他人的照顾。 以目标为导向的行为和降低生活质量。慢性疼痛的特征是感官、情绪和 认知功能障碍。阿片类药物，目前治疗慢性疼痛的标准，具有很高的成瘾倾向和 滥用它们会导致呼吸抑制和死亡。这凸显了改善疼痛的迫切需要。 治疗。有趣的是，一些接受阿片类药物治疗的慢性疼痛患者可以感觉到疼痛与其 负价，表明情绪-或情感-和认知症状的主要缓解 这是阿片类药物的止痛作用的基础。拟议项目的研究目标是描述一部小说的特征 疼痛活跃的皮质下-皮质环路，选择性地促进情感注意疼痛行为，并 确定其与内源性u阿片受体(µOR)系统的重叠。前扣带回皮质 (ACC)，一个以参与疼痛感知、情绪和认知而闻名的区域，在 将注意力引向疼痛。此外，由微或激活产生的阿片类止痛机制包括 部分地方性地定位于ACC。ACC接受来自杏仁基底外侧核(BLA)的输入，它包含一种疼痛- 治疗疼痛所需的情感价态合奏。然而，目前尚不清楚白血球蛋白是否具有疼痛影响价。 信息是在ACC中处理的，或者如果ACC中的阿片类信号可以扰乱BLA疼痛影响的输入 减少感受到的痛苦的负效应。目标1将决定伤害感受的必要性和充分性- Active Bla(BLAnoci)传入ACC驱动疼痛情绪注意行为的体内光遗传效应 接近。作为补充，BLAnoci输入到ACC的突触连接将使用 光遗传引导的体外脑片电生理学。目标2将测试µOR的必要性和充分性- 表达伤害性活性的ACC神经元，以逆转慢性疼痛受损的情感注意行为。这个 使用阿片类药物治疗慢性疼痛引起的巨大情感和认知需求有助于 持续的阿片类药物流行。靶向皮质阿片受体和伤害性感受活动回路选择性减少 疼痛的情绪成分可能是一种有效的治疗方法，实现这一长期目标 研究确定慢性疼痛的非成瘾疗法。完成这项奖学金将实现 培训目标是扩大麦考尔博士的实验专业知识，使她成为 新出现的痛感领域。

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.