Immune regulation of morphine-induced dependence in early development

描述（由申请人提供）：新生儿重症监护室中50-80%的婴儿在治疗结束时依赖阿片类药物。目前最好的医疗做法是提供递减量的阿片类药物，以逐渐减少婴儿患者的药物。因此，这种住院治疗对卫生保健系统构成了沉重的负担，对孩子留在医院的家庭构成了情感负担，对新生儿的后续发育产生了未知的后果。因此，新生儿阿片类药物依赖是一个重要的临床和公共卫生问题，需要新的治疗方法。我们对新生儿的阿片类药物依赖知之甚少，只知道它与成人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。这种相互作用是否存在于婴儿中还没有研究过，因此不知道，尽管这些婴儿中感染有多常见。我们在大鼠模型中的大量初步数据表明，在断奶前后的慢性吗啡治疗期间激活免疫系统可以消除戒断的身体和情感方面。同样的免疫激活治疗在非常年幼的幼鼠中没有效果。这些行为变化伴随着脊髓和大脑中免疫标记物表达的年龄依赖性差异。在这个探索性的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/戒断的幼鼠中的作用。我们提出了仔细的行为分析，我们已经开发了多年来衡量阿片类药物戒断的行为和情感成分。我们评估吗啡治疗婴儿的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鼠（7日龄;人类相当于~足月婴儿）的戒断反应，随着动物成熟，免疫系统-阿片类相互作用开始以与成年大鼠相似的方式发挥作用。我们的后续机制的假设是，Toll样受体4（TLR 4）介导的阿片类药物和免疫系统的相互作用，以调节阿片类药物依赖的年龄较大的婴儿，但没有后果的年轻的婴儿。为了验证这些假设，我们提出了药理学治疗和突变小鼠的测试，以了解免疫系统的作用，特别是在阿片类药物依赖的婴儿TLR 4受体。这项工作的完成将确定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。在确定免疫调节在阿片类药物依赖性婴儿中是否有效时，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基于免疫的治疗剂用于治疗婴儿患者的阿片类药物依赖。

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R21 application, we propose multiple analytic approaches to define the role of the immune system in morphine dependent/withdrawn infant rats.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