Age Differences of Brain Circuits Mediating Morphine Effect & Morphine Tolerance

介导吗啡效应的大脑回路的年龄差异

基本信息

批准号：
8139077
负责人：
DUSICA BAJIC
金额：
$ 4.22万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8139077
关键词：
Absence of pain sensation Acute Adult Age Analgesics Anesthesia procedures Appearance Area Attenuated Brain Cells Child Childhood Chronic Clinical Dependence Development Dose Foundations Future Goals Immediate-Early Genes Individual Infant Intensive Care Intervention Lead Location Mainstreaming Malignant Neoplasms Mediating Mediator of activation protein Medicine Methods Midbrain structure Modeling Molecular Morphine Neuromodulator Neurons Newborn Infant Nitric Oxide Nitric Oxide Synthase Opioid Pain Pain management Pathway interactions Patients Pattern Perioperative Pharmaceutical Preparations Population Postoperative Pain Predisposition Protein Isoforms Proteins Rattus Research Role Site Staging age difference age group age related aged attenuation base behavior measurement cancer pain chronic pain clinical practice density dosage effective therapy improved insight juvenile animal midbrain central gray substance neonate neurochemistry novel postnatal public health relevance pup research study response tool

项目摘要

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.

描述（由申请人提供）：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迅速发展。拟议研究的广泛长期目标是了解发育中大脑的耐受性的潜在机制，从而改善疼痛治疗。导水管周围灰质腹外侧区（vlPAG）是脊髓上疼痛调节通路的关键组成部分，该区域的可塑性与镇痛耐受性密切相关。该提案的重点是了解年轻、中年和成年大鼠之间 vlPAG 的耐受性适应有何不同。第一个目标是立即早期基因 Fos 的出现将被用作神经元激活的标记。 Fos 外观随年龄和药物治疗的变化将与耐受性行为测量相关。这些结果将为了解脊髓上机制如何随年龄差异对吗啡耐受性做出贡献奠定基础，并为相关细胞群的神经化学鉴定提供工具。第二个目标是研究神经元一氧化氮合酶 (nNOS) 同工型在耐受性中的作用。尽管 nNos 的激活与耐受性密切相关，但它在不同年龄组的 vlPAG 中的作用仍然知之甚少。这两个目标的结果将为年龄依赖性耐受机制的长期研究奠定基础。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，并将带来新的临床干预措施，以改善随年龄变化的疼痛、阿片类药物耐受性和依赖性的治疗。公共卫生相关性：尽管新生儿、婴儿和儿童明显会迅速增加阿片类药物剂量并更快地产生耐受性，但阿片类药物仍然是儿科人群围手术期、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日常临床实践密切相关的及时话题。该项目使用大鼠模型检查介导阿片类药物作用的神经元回路，以识别成人和发育中大脑机制之间的差异。