Immune regulation of morphine-induced dependence in early development

描述(由申请人提供)：新生儿重症监护病房中50%-80%的婴儿在治疗结束时依赖鸦片类药物。目前最好的医疗实践是提供数量不断减少的阿片类药物，以逐渐减少婴儿患者的药物用量。因此，这延长了住院时间，对保健系统构成重大负担，对孩子仍在医院的家庭造成情感负担，并对新生儿的后续发育产生未知的后果。因此，新生儿对阿片类药物的依赖是一个重大的临床和公共卫生问题，需要新的治疗方法。我们对新生儿阿片类药物依赖知之甚少，除了它与成人阿片类药物依赖的重要机制不同，阿片类药物与免疫系统之间存在相互作用。这种相互作用在婴儿中是否存在还没有被研究，因此也不清楚，尽管这些婴儿中的感染是多么普遍。我们在一只大鼠模型中的大量初步数据表明，在戒断周围的慢性吗啡治疗期间激活免疫系统会恶化戒断的身体和情感方面。同样的免疫激活治疗对幼年大鼠没有任何效果。伴随着这些行为变化的是脊髓和大脑中免疫标记物表达的年龄差异。在R21的这一探索性应用中，我们提出了多种分析方法来确定免疫系统在吗啡依赖/戒断幼鼠中的作用。我们提出了多年来开发的仔细的行为分析方法，以衡量阿片类药物戒断的行为和情感成分。我们评估了接受吗啡治疗的婴儿大脑和脊髓中免疫标记物和促炎细胞因子的mRNA和蛋白质。我们的工作假设是，上调或下调免疫系统不会改变幼年幼鼠(7天大；人类相当于足月婴儿)的戒断，随着动物的成熟，免疫系统-阿片类药物的相互作用开始以与成人相似的方式发挥作用。我们的机械性后续假说是，Toll样受体4(TLR4)介导阿片类药物和免疫系统的相互作用，以调节较大婴儿的阿片类药物依赖，但对较小的婴儿没有影响。为了验证这些假说，我们提出了药物治疗和突变小鼠的测试，以了解免疫系统的一般作用，特别是TLR4受体在阿片依赖婴儿中的作用。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变化。在确定免疫调节对阿片类药物依赖婴儿是否有效时，我们将提供临床前数据，以指导临床决定是否应该开发和实施基于免疫的疗法来治疗婴儿阿片类药物依赖患者。

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R21 application, we propose multiple analytic approaches to define the role of the immune system in morphine dependent/withdrawn infant rats.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.