The effects of gestational opioid exposure on the maternal brain, behavior and microbiome

妊娠期阿片类药物暴露对母体大脑、行为和微生物组的影响

• 批准号: 10671077
• 负责人: Susanne Brummelte
• 金额: $ 33.67万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671077
• 关键词: 3-Dimensional; Acute; Address; Affect; Agonist; Animal Model; Animals; Area; Behavior; Behavior Control; Birth; Brain; Brain region; Buprenorphine; Caring; Cell Nucleus; Child; Clinical; Conceptions; Data; Development; Dopamine; Ensure; Epidemic; Exposure to; Female; Fostering; Glutamates; Goals; Health; Heroin; High Pressure Liquid Chromatography; Human; Hypothalamic structure; Illicit Drugs; Image; Imaging Techniques; Incentives; Infant; Intervention; Knowledge; Life Experience; Light; Maps; Maternal Behavior; Maternal Exposure; Mediating; Methadone; Microscopy; Morphine; Mothers; Neurobiology; Neurons; Neuropeptides; Neurotransmitters; Nulliparity; Opiate Addiction; Opioid; Opioid replacement therapy; Organ; Outcome; Oxytocin; Pattern; Perception; Perinatal; Perinatal Exposure; Pharmaceutical Preparations; Pharmacodynamics; Physiology; Play; Postpartum Period; Pregnancy; Pregnant Women; Prevention strategy; Public Health; Rattus; Regulation; Reporting; Research; Resolution; Rewards; Rodent; Rodent Model; Role; Science; Solvents; Survival Rate; System; Translations; United States; Woman; adverse outcome; antagonist; beta diversity; biological adaptation to stress; child bearing; clinically relevant; cohort; comparison control; effectiveness evaluation; endogenous opioids; fetal opioid exposure; gut microbiome; gut-brain axis; improved; infant outcome; kappa receptors; marginalized population; maternal caregiving; maternal outcome; medication for opioid use disorder; microbiome; microbiome alteration; microbiota; mortality; motherhood; mu receptors; neglect; neurobiological mechanism; neurochemistry; offspring; opioid abuse; opioid epidemic; opioid exposure; opioid use; opioid use disorder; optimal treatments; pain sensitivity; perinatal period; prevent; pup; receptor; response; reward circuitry; sex; synthetic opioid

Opioid use disorder (OUD) is a global epidemic affecting a high proportion of child-bearing women. The drastic 4-fold increase in OUD among pregnant women from 1999-2014 has promoted opioid maintenance therapies (OMT) such as buprenorphine (BUP) to mitigate effects associated with opioid abuse. BUP is a mixed (partial mu-receptor agonist/kappa-receptor antagonist) semi-synthetic OMT that produces better infant outcomes after gestational treatment as compared to other OMTs (i.e. methadone). However, effects of BUP on pregnant women transitioning to motherhood is not well understood. Endogenous opioids play a significant role in orchestrating neuronal adaptations within the maternal brain network (MBN) for the successful ‘switch’ from a nulliparous brain to a maternal brain to incentivize nurturing maternal behaviors from the dam. It is well known that exogenous opioid exposure to morphine (full mu-agonist) during gestation can alter the endogenous opioid system and disrupt maternal care. However, there is a knowledge gap about the effects of BUP on the endogenous opioid system during the transition to motherhood and thus on maternal care behavior in the context of OUD during pregnancy. The proposed studies aim to address this knowledge gap by implementing a translational rodent model to evaluate the effects of BUP compared to morphine on the maternal brain, behavior and the microbiome well as on the long-term outcome of the offspring. Female rats will be exposed to BUP and/or morphine in clinically relevant paradigms starting before conception and continued throughout early postpartum. Effects of gestational BUP and morphine exposure on neurochemical and activation pattern changes in the maternal brain will be evaluated using state of the art imaging techniques. We will also evaluate the effectiveness of oxytocin as a potential intervention to increase maternal-offspring interaction in opioid- exposed dams and investigate the role of the microbiome in the long-term health outcome of exposed offspring. Our proposal will be able to add to the preliminary human findings on altered functional connectivity in buprenorphine-exposed mothers by using ‘whole (half) brain activity mapping’ which will allow us to simultaneously illuminate activity at cellular resolution in several brain areas of the MBN and compare patterns between opioid-exposed and control dams and investigate associations with changes in maternal behaviors. We expect that perinatal exposure to BUP inhibits the neuronal ‘switch’ from aversive to rewarding perception of pups that is necessary to initiate appropriate maternal behavior thus subsequently influencing offspring survival. The scale of the opioid epidemic requires an urgent response in order to promote treatment of OUD in pregnancy within an already marginalized population. We hope to advance science on the consequences of opioid drug use/therapy during gestation and to apply these outcomes toward clinical knowledge to improve public health via effective translation, implementation, and dissemination of our scientific research findings.

阿片类药物使用障碍 (OUD) 是一种全球流行病，影响很大比例的育龄妇女。 1999 年至 2014 年间，孕妇 OUD 增加了 4 倍，促进了阿片类药物维持治疗 (OMT)，如丁丙诺啡 (BUP)，可减轻与阿片类药物滥用相关的影响，是一种混合（部分）药物。 mu 受体激动剂/kappa 受体拮抗剂）半合成 OMT，可在治疗后产生更好的婴儿结局 与其他 OMT（即美沙酮）相比，BUP 对妊娠的影响。 女性过渡为母亲的过程尚不清楚。 协调母体大脑网络（MBN）内的神经适应，以成功从母体“转换” 众所周知，将未产妇大脑与母体大脑相结合，以激励母体的养育行为。 妊娠期间外源性阿片类药物暴露于吗啡（全 mu 激动剂）可以改变内源性阿片类药物 然而，关于 BUP 对产妇护理的影响存在知识差距。 向母亲过渡期间的内源性阿片类药物系统及其对孕产妇护理行为的影响 拟议的研究旨在通过实施一项措施来解决这一知识差距。 转化啮齿动物模型，用于评估 BUP 与吗啡相比对母体大脑、行为的影响 以及微生物组对雌性大鼠暴露于 BUP 的长期结果的影响。 和/或吗啡在临床相关范例中从受孕前开始并持续整个早期 妊娠期 BUP 和吗啡暴露对神经化学和激活模式的影响。 我们还将使用最先进的成像技术来评估母体大脑的变化。 催产素作为增加阿片类药物中母子相互作用的潜在干预措施的有效性 暴露的母鼠并研究微生物组在暴露后代的长期健康结果中的作用。 我们的建议将能够补充人类关于功能连接的初步发现 通过使用“全（半）脑活动映射”，我们可以帮助暴露于丁丙诺啡的母亲 同时以细胞分辨率阐明 MBN 多个大脑区域的活动并比较模式 我们对暴露于阿片类药物的母鼠和对照母鼠之间进行了比较，并调查了它们与母亲行为变化的关联。 预计围产期接触 BUP 会抑制神经元从厌恶感知到奖励感知的“转换” 幼崽对于启动适当的母性行为是必要的，从而影响后代的生存。 阿片类药物流行的规模需要紧急应对，以促进妊娠期 OUD 的治疗 我们希望在已经边缘化的人群中推动有关阿片类药物后果的科学发展。 妊娠期间的使用/治疗，并将这些结果应用于临床知识，以改善公众健康 通过有效翻译、实施和传播我们的科学研究成果。