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围产期暴露于丁丙诺啡和羟考酮会损害新产母鼠的母性行为并增加神经炎症。

Peripartum buprenorphine and oxycodone exposure impair maternal behavior and increase neuroinflammation in new mother rats.

作者信息

Dye Courtney N, Webb Aliyah I, Fankhauser Madison P, Singleton Jordyn J, Kalathil Aravind, Ringland Amanda, Leuner Benedetta, Lenz Kathryn M

机构信息

Neuroscience Graduate Program, The Ohio State University, Columbus, OH, USA; Department of Psychology, The Ohio State University, Columbus, OH, USA.

Department of Psychology, The Ohio State University, Columbus, OH, USA.

出版信息

Brain Behav Immun. 2025 Feb;124:264-279. doi: 10.1016/j.bbi.2024.11.027. Epub 2024 Nov 27.

Abstract

7 % of pregnant people use opioids. Opioid use during pregnancy can negatively impact maternal and offspring health. Medications for opioid use disorder (MOUD), commonly buprenorphine, are the recommended treatment for opioid use disorder during pregnancy to prevent cycles of withdrawal and relapse. In addition to effects on opioid receptors, opioids have strong binding affinity to toll-like receptor (TLR) 4, an immune cell receptor, and thereby impact neuroinflammatory signaling. We have previously shown that neuroimmune alterations are important for the display of maternal behavior. Here, we used a rodent model to assess the impact of chronic peripartum opioid exposure or MOUD on maternal caregiving and neuroinflammation in the postpartum brain. Female rats were exposed to vehicle (VEH), buprenorphine (BUP) to model MOUD, or oxycodone (OXY), to model peripartum drug use, before, during, and after pregnancy. Opioid exposure reduced gestation length and maternal weight gain. Postpartum maternal caretaking behaviors, including pup retrieval, huddling and nursing, and pup-directed sniffing and licking, were reduced in opioid-exposed mothers. Following behavioral testing, tissue was collected from brain regions important for maternal caretaking, including the prefrontal cortex (PFC), nucleus accumbens (NAc), preoptic area (POA), amygdala (AMY), and periaqueductal grey (PAG). Immunofluorescent labeling showed that BUP increased astrocyte labeling, while OXY increased microglia labeling in the PAG, but not other regions. Gene expression analysis also showed regional and treatment differences in immune transcripts. BUP and OXY increased TLR4 in the PFC. BUP increased TNF in the NAc but decreased IL1β in the POA. OXY increased CD68 in the POA, and IL1β, TNF, and TLR4 in the PAG. Together, these results provide novel evidence of peripartum neuroimmune alterations following chronic opioid exposure that could be mediating maternal care deficits. This work provides a foundation to explore the extent to which modulation of neuroimmune activation may be a potential intervention for caregiving deficits in mothers exposed to opioids during pregnancy.

摘要

7%的孕妇使用阿片类药物。孕期使用阿片类药物会对母体和后代健康产生负面影响。用于治疗阿片类药物使用障碍(MOUD)的药物,通常是丁丙诺啡,是孕期阿片类药物使用障碍的推荐治疗方法,以防止戒断和复发循环。除了对阿片受体的作用外,阿片类药物与Toll样受体(TLR)4(一种免疫细胞受体)具有很强的结合亲和力,从而影响神经炎症信号传导。我们之前已经表明,神经免疫改变对母性行为的表现很重要。在这里,我们使用啮齿动物模型来评估围产期长期暴露于阿片类药物或MOUD对产后大脑中母性照料和神经炎症的影响。在怀孕前、怀孕期间和产后,将雌性大鼠暴露于载体(VEH)、用于模拟MOUD的丁丙诺啡(BUP)或用于模拟围产期药物使用的羟考酮(OXY)。阿片类药物暴露会缩短妊娠期并减少母体体重增加。在暴露于阿片类药物的母亲中,产后母性照料行为,包括找回幼崽、蜷缩和哺乳,以及针对幼崽的嗅闻和舔舐行为都会减少。行为测试后,从对母性照料很重要的脑区收集组织,包括前额叶皮质(PFC)、伏隔核(NAc)、视前区(POA)、杏仁核(AMY)和导水管周围灰质(PAG)。免疫荧光标记显示,BUP增加了星形胶质细胞标记,而OXY增加了PAG中的小胶质细胞标记,但其他区域没有。基因表达分析还显示了免疫转录本的区域和治疗差异。BUP和OXY增加了PFC中的TLR4。BUP增加了NAc中的TNF,但降低了POA中的IL1β。OXY增加了POA中的CD68,以及PAG中的IL1β、TNF和TLR4。总之,这些结果为围产期长期暴露于阿片类药物后神经免疫改变提供了新的证据,这些改变可能介导了母性照料缺陷。这项工作为探索调节神经免疫激活在多大程度上可能是对孕期暴露于阿片类药物的母亲照料缺陷的潜在干预措施奠定了基础。

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