Central amygdala CRF1 cells control nociception and anxiety-like behavior.
Central amygdala CRF1 cells control nociception and anxiety-like behavior.
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中央杏仁核 CRF1 细胞控制伤害感受和焦虑样行为。
DOI：
10.1038/s41386-023-01693-2
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Gilpin,NicholasW
中科院分区：
文献类型：
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作者：
Weera,MarcusM;Gilpin,NicholasW
中央杏仁核（CeA）调节情感状态和适应行为，在正常和病理条件下。啮齿动物研究表明，CeA中的细胞表达多种神经肽和神经肽受体，调节CeA细胞的活性。神经肽促肾上腺皮质激素释放因子（CRF）和CRF 1型受体（CRF 1）在CeA中密集表达[1]。CRF以高亲和力结合CRF 1，大量药理学研究表明，CeA中的这种信号传导事件促进焦虑和疼痛相关行为[2]。多年来，转化研究人员一直在探索CRF 1拮抗剂的治疗潜力，但在焦虑、抑郁和/或酒精使用障碍患者中进行的临床试验在很大程度上产生了负面结果（请参见参考文献10）。[3]用于讨论推进CRF 1拮抗剂作为治疗剂的潜在途径）[3，4]。尽管CRF 1拮抗剂在疼痛管理中的功效尚未得到验证，但这些化合物在管理人类焦虑和相关疾病方面缺乏成功，这突出了我们需要扩大对CRF系统如何调节模型动物和人类这些行为的理解。我们实验室的工作目前集中在阐明CRF 1细胞的特定亚群在大鼠应激、疼痛和成瘾相关行为中的作用。为此，我们最近开发了CRF 1-Cre大鼠，允许可视化和操作CRF 1细胞的特定群体[1]。使用这些动物，我们表明CeA CRF 1细胞的体内刺激增加了焦虑样行为并产生异常性疼痛[1]。这一发现表明，旨在调节CRF 1细胞（但不一定是CRF 1受体）的活性的治疗策略可能有助于管理焦虑和疼痛相关的状态和behaviors.In人类，关于CRF 1细胞的特定亚群在焦虑和疼痛中的作用的信息是稀缺的。其他研究，也许使用死后人体组织，是否CRF 1细胞亚群改变（例如，生物化学，形态学）在个人谁有焦虑和/或疼痛相关的疾病可能是有用的桥接临床前和转化研究。如果CeA（或其他群体）CRF 1细胞确实对介导人类焦虑和疼痛很重要，那么转基因CRF 1 Cre/报告啮齿动物将有助于确定这些细胞在焦虑和疼痛相关疾病状态中失调的分子/生化机制（例如，通过单细胞组学方法），可能导致发现新的可药用靶点。为了补充这些
The central amygdala (CeA) modulates affective states and adaptive behaviors, under both normal and pathological conditions. Rodent studies show that cells in the CeA express a variety of neuropeptides and neuropeptide receptors that modulate the activity of CeA cells. The neuropeptide corticotropin-releasing factor (CRF) and CRF type-1 receptors (CRF1) are densely expressed in the CeA [1]. CRF binds CRF1 with high affinity, and a large corpus of pharmacology studies show that this signaling event in the CeA promotes anxiety-and pain-related behaviors [2]. Translational researchers have been exploring the therapeutic potential of CRF1 antagonists for many years, but clinical trials in patients with anxiety, depression, and/or alcohol use disorder have largely yielded negative results (please see ref.[3] for a discussion on potential avenues for advancing CRF1 antagonists as therapeutics)[3, 4]. Although the efficacy of CRF1 antagonists in pain management remains untested, the lack of success of these compounds in managing anxiety and related conditions in humans highlight the need for expanding our understanding of how the CRF system modulates these behaviors in model animals and humans. Work in our lab is currently focused on elucidating the role of specific subpopulations of CRF1 cells in stress-, painand addiction-related behaviors in rats. To this end, we recently developed CRF1-Cre rats that permit visualization and manipulation of specific populations of CRF1 cells [1]. Using these animals, we showed that in vivo stimulation of CeA CRF1 cells increases anxiety-like behavior and produces allodynia [1]. This finding suggests that therapeutic strategies aimed at modulating the activity of CRF1 cells (but not necessarily CRF1 receptors) may be useful for managing anxiety and pain-related states and behaviors.In humans, information regarding the role of specific subpopulations of CRF1 cells in anxiety and pain is scarce. Additional studies, perhaps using postmortem human tissue, on whether subpopulations of CRF1 cells are altered (eg, biochemically, morphologically) in individuals who had anxiety-and/or painrelated disorders may be useful for bridging preclinical and translational studies. If CeA (or other populations of) CRF1 cells are indeed important for mediating anxiety and pain in humans, then transgenic CRF1 Cre/reporter rodents would be useful for identifying molecular/biochemical mechanisms by which these cells become dysregulated in anxiety-and pain-related disease states (eg, via single-cell omics approaches), potentially leading to the discovery of novel druggable targets. To complement these