Age Differences of Brain Circuits Mediating Morphine Effect & Morphine Tolerance

描述(申请人提供)：越来越多的证据表明，新生儿和婴儿对阿片类药物的耐受性发展迅速。这项拟议研究的广泛的长期目标是了解发育中的大脑中潜在的耐受机制，这将导致改善疼痛治疗。腹外侧中脑导水管周围灰质(VlPAG)是脊髓上痛觉调制通路的重要组成部分，该区域的可塑性与镇痛耐受密切相关。这项建议侧重于了解vlPAG在耐受情况下发生的适应在幼鼠、中年鼠和成年鼠之间的差异。在第一个目标中，一个即刻早期基因Fos的出现将被用作神经元激活的标志。随着年龄和药物治疗的变化，Fos的出现将与耐受性的行为指标相关。这一结果将为理解脊髓上机制如何随年龄而不同地促进吗啡耐受提供基础，并为相关细胞群体的神经化学鉴定提供工具。在第二个目的中，将研究神经元亚型一氧化氮合酶(NNOS)与耐受的关系。尽管nNOS的激活与耐受密切相关，但它在不同年龄段的vlPAG中的作用仍然知之甚少。这两个目标的结果将为长期研究依赖年龄的耐受机制提供基础。这是一个重要的研究领域，将为阿片类药物耐受的分子机制提供新的见解，并将导致新的临床干预措施，以改善疼痛、阿片类药物耐受和依赖的治疗，这些治疗因年龄而异。 公共卫生相关性：尽管新生儿、婴儿和儿童迅速增加阿片类药物的剂量并更快地形成耐受性，但阿片类药物仍然是儿科人群围术期、癌症和其他慢性疼痛的主流治疗方法。因此，阿片类药物耐受是一个与儿科医学和儿科麻醉的日常临床实践密切相关的及时课题。利用大鼠模型，该项目检查了介导阿片类药物效应的神经元电路，以确定成人和发育中的大脑机制之间的差异。

DESCRIPTION (provided by applicant): Accumulating evidence suggests that opioid tolerance rapidly develops in neonates and infants. The broad long-term objective of the proposed research is to understand underlying mechanisms of tolerance in the developing brain that would lead to improved pain treatment. The ventrolateral periaqueductal gray (vlPAG) is a key component of supraspinal pain-modulatory pathways, and plasticity in this area is strongly implicated in analgesic tolerance. This proposal focuses on understanding how adaptations in the vlPAG that occur with tolerance may differ between young, intermediate-aged and adult rats. In the first aim, the appearance of an immediate early gene, Fos, will be used as a marker of neuronal activation. Changes in the appearance of Fos with age and drug treatment will be correlated with behavioral measures of tolerance. The results will provide a basis for understanding how supraspinal mechanisms differentially contribute to morphine tolerance with age, and provide a tool for neurochemical identification of relevant cell populations. In the second aim, the involvement of the neuronal isoform of nitric oxide synthase (nNOS) in tolerance will be investigated. Although activation of nNos has been strongly implicated in tolerance, it's role in the vlPAG within different age groups remains poorly understood. The results of both aims will provide a foundation for long-term research into age- dependent mechanisms of tolerance. It is an important area of research that will provide novel insights into molecular mechanisms of opioid tolerance and will lead to new clinical interventions to improve treatment of pain, opioid tolerance and dependence that differ with age. PUBLIC HEALTH RELEVANCE: Although it has became apparent that neonates, infants, and children rapidly escalate opioid dose and develop tolerance faster, opioids remain mainstream therapy for perioperative, cancer and other chronic pain for pediatric populations. Therefore, opioid tolerance is a timely topic of great relevance to daily clinical practice of pediatric medicine and pediatric anesthesia. Using a rat model, this project examines neuronal circuits mediating opioid effects to identify differences between the adult and the developing brain mechanisms.