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中枢通路的协调活动驱动阿片类药物的关联镇痛耐受。

Coordinated activity of a central pathway drives associative opioid analgesic tolerance.

机构信息

Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China.

Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei 230088, China.

出版信息

Sci Adv. 2023 Feb 10;9(6):eabo5627. doi: 10.1126/sciadv.abo5627. Epub 2023 Feb 8.

DOI:10.1126/sciadv.abo5627
PMID:36753548
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9908028/
Abstract

Opioid analgesic tolerance, a root cause of opioid overdose and misuse, can develop through an associative learning. Despite intensive research, the locus and central pathway subserving the associative opioid analgesic tolerance (AOAT) remains unclear. Using a combination of chemo/optogenetic manipulation with calcium imaging and slice physiology, here we identify neuronal ensembles in a hierarchically organized pathway essential for AOAT. The association of morphine-induced analgesia with an environmental condition drives glutamatergic signaling from ventral hippocampus (vHPC) to dorsomedial prefrontal cortex (dmPFC) cholecystokininergic (CCKergic) neurons. Excitation of CCKergic neurons, which project and release CCK to basolateral amygdala (BLA) glutamatergic neurons, relays AOAT signal through inhibition of BLA μ-opioid receptor function, thereby leading to further loss of morphine analgesic efficacy. This work provides evidence for a circuit across different brain regions distinct for opioid analgesic tolerance. The components of this pathway are potential targets to treat opioid overdose and abuse.

摘要

阿片类药物镇痛耐受是阿片类药物过量和滥用的根本原因，可以通过联想学习发展。尽管进行了深入研究，但尚不清楚与联想阿片类药物镇痛耐受（AOAT）相关的中枢途径和中枢位置。在这里，我们使用化学/光遗传学操作与钙成像和切片生理学相结合，确定了一个分层组织通路中的神经元集合，该通路对于 AOAT 至关重要。吗啡诱导的镇痛与环境条件的关联会驱动腹侧海马体（vHPC）到背侧前额叶皮层（dmPFC）胆囊收缩素能（CCKergic）神经元的谷氨酸能信号传导。CCKergic 神经元的兴奋会将 CCK 投射并释放到杏仁核基底外侧核（BLA）谷氨酸能神经元，从而通过抑制 BLA μ-阿片受体功能来传递 AOAT 信号，进而导致吗啡镇痛效果进一步丧失。这项工作为不同脑区之间的阿片类药物镇痛耐受的特定环路提供了证据。该途径的组成部分可能是治疗阿片类药物过量和滥用的潜在靶点。

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