Modulating pain through cortical endogenous opioid circuits

项目摘要 疼痛对生命至关重要，通过将注意力集中在急性损伤或威胁上，发挥着重要的保护作用 疼痛的来源。然而，无情的慢性疼痛需要无情的关注，防止出席其他 目标导向行为和降低生活质量。慢性疼痛的特点是感觉，情绪， 认知功能障碍阿片类药物是目前治疗慢性疼痛的标准药物，具有很高的成瘾倾向， 滥用可导致呼吸抑制和死亡。这突出了对改善疼痛的迫切需求 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 负效价，表明情绪或情感和认知症状的缓解主要是 是阿片类药物镇痛作用的基础该项目的研究目标是描述一种新的 疼痛激活的皮层下-皮层回路，选择性地促进情感注意疼痛行为， 确定其与内源性μ阿片受体（μOR）系统的重叠。前扣带皮层 (ACC)，一个以参与疼痛感知，情绪和认知而闻名的区域，在以下方面起着执行作用： 将注意力转移到疼痛上。此外，由µOR激活引起的阿片类镇痛机制是 ACC接受来自基底外侧杏仁核（BLA）的输入，BLA包含疼痛- 影响疼痛所需的效价整体。然而，尚不清楚BLA疼痛是否影响效价 信息在ACC中处理，或者如果ACC中的阿片样物质信号可以破坏这种BLA疼痛影响输入， 减少对疼痛的负面感受。目标1将确定伤害感受的必要性和充分性- 用体内光遗传学方法研究ACC的主动BLA（BLAnoci）输入在驱动疼痛情感注意行为中的作用 approach.作为补充，BLAnoci输入到ACC的突触连接性将使用以下来表征： 光遗传学引导的离体切片电生理学。目标2将测试µOR的必要性和充分性- 表达，伤害感受活性ACC神经元，以逆转慢性疼痛受损的情感注意行为。的 使用阿片类药物来治疗由慢性疼痛引起的巨大的情感和认知需求， 持续的阿片类药物流行靶向皮质阿片受体和伤害感受活性回路， 疼痛的情感成分可能是一种有效的治疗方法，可以实现长期目标。 研究确定慢性疼痛的非成瘾性疗法。完成该奖学金将实现 培训目标是扩大麦考尔博士的实验专业知识，并建立她作为一个专家， 疼痛影响的新兴领域。

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.