Immune regulation of morphine-induced dependence in early development

吗啡诱导的早期发育依赖的免疫调节

• 批准号: 8852586
• 负责人: GORDON Alfred BARR
• 金额: $ 20.69万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852586
• 关键词: Acute; Adult; Adverse effects; Affect; Affective; Age; Basic Science; Behavior; Behavioral; Behavioral Assay; Brain; Child; Chronic; Clinical; Data; Dependence; Development; Emotional; Family; Goals; Health; Healthcare; Healthcare Systems; Hospitalization; Hospitals; Human; Immune; Immune system; Immunologic Markers; Infant; Infection; Inflammatory; Injection of therapeutic agent; Lead; Length of Stay; Lipopolysaccharides; Mediating; Medical; Messenger RNA; Methadone; Minocycline; Modeling; Morphine; Morphine Dependence; Mus; Mutant Strains Mice; Naltrexone; Nature; Neonatal Intensive Care Units; Newborn Infant; Opiate Addiction; Opiates; Opioid; Opioid Receptor; Patients; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Population; Practice Management; Proteins; Public Health; Rattus; Regulation; Role; Signal Transduction; Spinal Cord; Sterile coverings; Substance Withdrawal Syndrome; Testing; Therapeutic; Therapeutic Effect; Translating; Weaning; Withdrawal; Work; age related; aged; base; behavior measurement; cost; cytokine; follow-up; immune function; immunoregulation; maternal drug use; mature animal; neonate; novel; novel therapeutic intervention; opiate tolerance; postnatal; pre-clinical; pup; receptor; toll-like receptor 4

DESCRIPTION (provided by applicant): Between 50-80% of infants in the neonatal intensive care unit are dependent on opiates by the end of their medical treatment. Best current medical practice is to provide declining amounts of opiates to taper the infant patient off the drugs. As such, this prolongs hospitalization and constitutes a significant burden on the health care system, and an emotional burden on the family whose child remains in the hospital, and has unknown consequences for subsequent development of the newborn. Therefore opiate dependence in the neonate is a substantial clinical and public health problem in need of new therapeutic approaches. We know little about opiate dependence in the neonate, except that it differs in important mechanisms from dependence in the adult, when there is interplay between opioids and the immune system. Whether that interplay is present or not in the infant has not been studied and thus is not known, despite how common infection is in these babies. Our extensive preliminary data in a rat model show that activating the immune system during chronic morphine treatment around weaning worsens both the physical and affective aspects of withdrawal. The same immune activating treatment in very young infant rats has no effect. These behavioral changes are accompanied by age-dependent differences in the expression of immune markers in the spinal cord and brain. In this exploratory R21 application, we propose multiple analytic approaches to define the role of the immune system in morphine dependent/withdrawn infant rats. We propose careful behavioral assays that we have developed over the years to measure the behavioral and affective components of opiate withdrawal. We assess mRNA and protein for immune markers and proinflammatory cytokines in the brain and spinal cord of morphine treated infants. Our working hypothesis is that up- or down-regulating the immune system will not alter withdrawal in the young infant rat (7 days of age; human equivalent is ~full term infant), and that as the animal matures, immune system-opioid interactions begin to function in ways similar to those of the adult. Our mechanistic follow-up hypothesis is that the toll-like-receptor 4 (TLR4) mediates the interactions of opiates and the immune system to modulate opiate dependence in the older infant but has no consequence for the younger infant. To test these hypotheses, we propose pharmacological treatments and tests with mutant mice to understand the role the immune system in general and of the TLR4 receptors in particular in opiate dependent infants. The completion of this work will define how the interactions between opioid and immune systems change as the animal matures. In determining if immune modulation is effective or not in the opiate dependent infant, we will provide preclinical data to direct clinical decisions as to whether or not immune based therapeutics should be developed and implemented for the treatment of opiate dependence in infant patient.

描述（由申请人提供）：在新生儿重症监护病房中，有50-80％的婴儿在医疗治疗结束时依赖阿片类药物。当前的最佳医疗实践是提供减少数量的阿片类药物，以使婴儿患者从药物中缩减。因此，这延长了住院治疗，并构成了医疗保健系统的巨大负担，以及对孩子留在医院的家庭的情感负担，并且对随后的新生儿发展产生了未知的后果。因此，鸦片对新生儿的依赖性是需要新的治疗方法的实质性临床和公共卫生问题。我们对新生儿的鸦片依赖性知之甚少，只是当阿片类药物与免疫系统之间存在相互作用时，重要机制与成人的依赖性不同。尽管这些婴儿的常见感染是多么常见，但尚未研究婴儿中的相互作用。我们在大鼠模型中广泛的初步数据表明，在断奶周围慢性吗啡治疗期间激活免疫系统会使戒断的身体和情感方面都恶化。在非常年轻的婴儿大鼠中相同的免疫激活治疗没有作用。这些行为变化伴随着脊髓和大脑中免疫标记表达的年龄依赖性差异。在此探索性R21应用中，我们提出了多种分析方法来定义免疫系统在吗啡依赖性/撤回婴儿大鼠中的作用。我们提出了多年来开发的仔细的行为分析，以衡量阿片类药物戒断的行为和情感组成部分。我们评估了吗啡治疗的婴儿的脑和脊髓中的免疫标记和促炎细胞因子的mRNA和蛋白质。我们的工作假设是，上或下调免疫系统不会改变婴儿大鼠的年轻大鼠的戒断（7天；人类等效的是〜完全期婴儿），并且随着动物的成熟，免疫系统 - 阿片类药物的相互作用开始在类似于成年人类似的方式中起作用。我们的机械随访假设是，Toll样受体4（TLR4）介导了阿片类药物的相互作用和免疫系统的相互作用，以调节老年婴儿的鸦片依赖性，但对年轻婴儿没有影响。为了检验这些假设，我们建议使用突变小鼠的药理学治疗和测试，以了解一般的免疫系统和TLR4受体的作用，尤其是在阿片相关的婴儿中。这项工作的完成将定义阿片类药物和免疫系统之间的相互作用如何随着动物的成熟而发生变化。在确定免疫调节是否在鸦片依赖的婴儿中有效，我们将提供临床前数据，以指导临床决策，即是否应开发和实施是否应开发并实施以治疗婴儿患者的鸦片依赖性。