The Institute of Academic Anaesthesia, Division of Cellular and Systems Medicine, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, United Kingdom.
Pain. 2023 Oct 1;164(10):2253-2264. doi: 10.1097/j.pain.0000000000002925. Epub 2023 May 10.
Exposure to severely stressful events during childhood is associated with poor health outcomes in later life, including chronic pain and substance use disorder. However, the mediators and mechanisms are unclear. We investigated the impact of a well-characterized mouse model of early-life adversity, fragmented maternal care (FC) between postnatal day 2 and 9, on nociception, inflammatory hypersensitivity, and responses to morphine. Male and female mice exposed to FC exhibited prolonged basal thermal withdrawal latencies and decreased mechanical sensitivity. In addition, morphine had reduced potency in mice exposed to FC and their development of tolerance to morphine was accelerated. Quantitative PCR analysis in several brain regions and the spinal cords of juvenile and adult mice revealed an impact of FC on the expression of genes encoding opioid peptide precursors and their receptors. These changes included enhanced abundance of δ opioid receptor transcript in the spinal cord. Acute inflammatory hypersensitivity (induced by hind paw administration of complete Freund's adjuvant) was unaffected by exposure to FC. However, after an initial recovery of mechanical hypersensitivity, there was a reappearance in mice exposed to FC by day 15, which was not seen in control mice. Changes in nociception, morphine responses, and hypersensitivity associated with FC were apparent in males and females but were absent from mice lacking δ receptors or β-arrestin2. These findings suggest that exposure to early-life adversity in mice enhances δ receptor expression leading to decreased basal sensitivity to noxious stimuli coupled with accelerated morphine tolerance and enhanced vulnerability to persistent inflammatory hypersensitivity.
儿童时期经历严重的压力事件与晚年健康状况不佳有关，包括慢性疼痛和物质使用障碍。然而，其中的介体和机制尚不清楚。我们研究了一种经过充分特征描述的幼年逆境小鼠模型，即产后第 2 天至第 9 天期间的母婴分离（FC），对痛觉、炎症性过敏反应和吗啡反应的影响。暴露于 FC 的雄性和雌性小鼠表现出基础热撤退潜伏期延长和机械敏感性降低。此外，吗啡对 FC 暴露的小鼠的效力降低，其对吗啡的耐受性发展加快。幼年和成年小鼠的几个大脑区域和脊髓中的定量 PCR 分析显示，FC 对编码阿片肽前体及其受体的基因表达有影响。这些变化包括脊髓中 δ 阿片受体转录本的丰度增加。急性炎症性过敏反应（通过后爪给予完全弗氏佐剂诱导）不受 FC 暴露的影响。然而，在机械过敏反应最初恢复后，在 FC 暴露的小鼠中第 15 天再次出现，而在对照小鼠中未出现。与 FC 相关的痛觉、吗啡反应和过敏反应的变化在雄性和雌性小鼠中均可见，但在缺乏 δ 受体或β-arrestin2 的小鼠中不存在。这些发现表明，幼年时期暴露于逆境会增强 δ 受体表达，导致对有害刺激的基础敏感性降低，同时加速吗啡耐受和增强对持续性炎症过敏反应的易感性。
