mTOR, A new target for opioid-induced togerance and hyperalgesia

mTOR，阿片类药物引起的耐受和痛觉过敏的新靶点

基本信息

批准号：
8738282
负责人：
Yuan-Xiang Tao
金额：
$ 33.47万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-15 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8738282
关键词：
1-Phosphatidylinositol 3-Kinase Address Adverse effects Analgesics Attenuated Binding Proteins Chronic Clinical Development Dose Eukaryotic Initiation Factor-4E FDA approved Genetic Gold Hyperalgesia Injection of therapeutic agent Lead Maintenance Malignant Neoplasms Mediating Molecular Morphine Neuraxis Neuronal Plasticity Nociception Operative Surgical Procedures Opioid Pain Pain management Pathway interactions Patient Care Patients Peripheral Pharmaceutical Preparations Pharmacological Treatment Phosphorylation Posterior Horn Cells Process Protein Biosynthesis Protein Kinase Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Rattus Receptor Activation Spinal Spinal Anesthesia Testing Time Translation Initiation Translations Work allodynia clinical application clinical efficacy dorsal horn improved inhibitor/antagonist mTOR protein mu opioid receptors nerve injury novel novel therapeutics overexpression prevent public health relevance receptor ribosomal protein S6 kinase 1

项目摘要

DESCRIPTION (provided by applicant): Understanding the mechanisms that underlie opioid-induced analgesic tolerance and hyperalgesia is important for developing novel therapeutic strategies to achieve more effective pain management. The changes in dorsal horn neuronal plasticity that occur after chronic opioid exposure are believed to underlie the induction and maintenance of opioid-induced tolerance and hyperalgesia. Mammalian target of rapamycin (mTOR), a serine-threonine protein kinase, controls protein translation via phosphorylation of specific downstream effectors, such as 4E-BP1 and S6K1. Our preliminary work indicates that mu receptor/PI3K/Akt- mediated activation of dorsal horn mTOR participates in the formation of neuronal plasticity through mTOR- triggered initiation of protein translation during chronic morphine exposure. These novel discoveries suggest that dorsal horn mTOR activation is required for the development and maintenance of morphine-induced tolerance and hyperalgesia. This proposal will determine whether and how mTOR and its downstream effectors are activated in dorsal horn neurons under chronic morphine exposure and whether and how this activation contributes to the development and maintenance of morphine-induced analgesic tolerance and hyperalgesia. In Specific Aim 1, we will examine (a) whether mTOR, S6K1, 4E-BP1, PI3K, and Akt are activated through mu receptor activation in dorsal horn following repeated morphine injections; (b) whether PI3K and Akt mediate mu receptor-triggered activation of mTOR, S6K1, and 4E-BP1 in dorsal horn neurons during chronic morphine exposure; and (c) whether the PI3K/Akt/mTOR pathway is activated in mu receptor-expressing and nociceptive dorsal horn neurons following repeated morphine injection. In Specific Aim 2, we will define whether spinal mu receptor-dependent activation of the PI3K/Akt/mTOR pathway contributes to mechanism of morphine tolerance and hyperalgesia through mTOR-triggered dorsal horn protein synthesis. We will examine (a) time-dependent increases in translation initiation activity, nascent protein synthesis, and some known tolerance-associated key proteins in dorsal horn neurons following chronic morphine exposure and (b) whether these increases could be blocked by inhibition of spinal mu receptor-triggered activation of the PI3K/Akt/mTOR pathway. In Specific Aim 3, we will determine whether spinal mTOR and the translation initiation that it triggers are required for the development and maintenance of morphine-induced tolerance and hyperalgesia. The effects of pharmacologic inhibition of spinal mTOR, genetic knockdown of spinal mTOR and S6K1, or over- expression of dorsal horn 4E-BP1 on the development and maintenance of morphine-induced tolerance and hyperalgesia will be examined. The proposed studies will provide major conceptual advances to our understanding of the molecular mechanism of morphine-induced analgesic tolerance and hyperalgesia. Because mTOR inhibitors are FDA-approved drugs, our studies may also have a strong potential clinical application in treating and/or preventing opioid-induced analgesic tolerance and hyperalgesia.

描述（由申请人提供）：了解阿片类药物诱导的镇痛耐受性和Hypergersia的机制对于制定新的治疗策略以实现更有效的疼痛管理很重要。据信，慢性阿片类药物暴露后发生的背角神经元可塑性的变化是基于阿片类药物诱导的耐受性和超痛性的诱导和维持。雷帕霉素的哺乳动物靶标（MTOR）是一种丝氨酸 - 硫代蛋白激酶，通过特定下游效应子（例如4E-BP1和S6K1）的磷酸化来控制蛋白质的翻译。我们的初步工作表明，MU受体/PI3K/AKT介导的背角mTOR激活参与通过MTOR触发慢性吗啡暴露期间蛋白质翻译的开始来形成神经元可塑性。这些新颖的发现表明，在形成诱导的耐受性和痛觉过敏的发展和维持中需要背角mTOR激活。该建议将决定是否以及如何在慢性吗啡暴露下在背角神经元中激活MTOR及其下游效应子，以及这种激活是否以及如何有助于吗啡诱导的镇痛耐受性和Hyperangesia的发展和维持。在特定目标1中，我们将检查（a）MTOR，S6K1，4E-BP1，PI3K和AKT是否在重复吗啡注射后通过背角中的MU受体激活激活；（b）在慢性吗啡暴露期间，PI3K和AKT是否介导了背角神经元中MTOR，S6K1和4E-BP1的MU受体触发的激活；（c）在反复注射吗啡后，PI3K/AKT/MTOR途径是否在表达MU受体的表达和伤害性背角神经元中激活。在特定的目标2中，我们将定义脊柱MU受体依赖性PI3K/AKT/MTOR途径是否有助于通过MTOR触发的背角蛋白合成的机制和杀伤性的机制。我们将检查（a）慢性吗啡暴露后，在背角神经元中翻译起始活性，新生蛋白合成的时间依赖性增加，以及一些已知的耐受性相关的关键蛋白，以及（b）是否可以通过抑制脊柱MU受体受体激活的PI3K/akt/akt/mmtor pation来阻止这些增加。在特定的目标3中，我们将确定脊柱MTOR是否及其触发的翻译开始是否需要用于发展和维持吗啡诱导的耐受性和痛觉过敏。将检查药理学抑制脊柱MTOR，脊髓MTOR和S6K1的遗传敲低或背角4E-BP1的过度表达对吗啡诱导的耐受性和超痛觉的发展。拟议的研究将为我们理解吗啡诱导的镇痛耐受性和痛觉过敏的分子机制提供了重大的概念进步。由于MTOR抑制剂是FDA批准的药物，因此我们的研究在治疗和/或预防阿片类药物诱导的镇痛耐受性和痛苦。