Integrative And Molecular Studies Of Pain & Pain Control

疼痛的综合和分子研究

• 批准号: 6814532
• 负责人: Michael J. Iadarola
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6814532
• 关键词: Adenoviridae; C fiber; Pseudomonas; analgesia; brain imaging /visualization /scanning; chimeric proteins; chronic pain; clinical research; exotoxins; gene therapy; genetic transcription; human subject; human therapy evaluation; ion transport; molecular cloning; molecular pathology; neurogenetics; neuropeptides; recombinant proteins; spinal cord; transfection; transfection /expression vector

Our research program addresses basic molecular and physiological processes of nociceptive transmission in the central nervous system. The molecular research is performed in animal and in vitro cell-based models. We concentrate on the primary afferent pain sensing neurons and their connections in the dorsal spinal cord. The dorsal spinal cord is the first site of synaptic connections for nociceptive information processing and our research has identified it as a locus of neuronal plasticity and altered gene expression in persistent pain states. Our aim is to understand the molecular and cell biological mechanisms of acute and chronic pain at the "entry level" in the nervous system. The regulation of transduction of physical pain stimuli is also under investigation using cloned thermal and chemo-responsive ion channels ectopically expressed in heterologous cell systems and naturally expressed in primary cultures of dorsal root ganglion. Novel methods for controlling nociceptive transmission that emerge from this basic research are addressed in a translational research program. Two main basic science issues are being investigated. The first centers on the molecular mechanisms of pain transduction through the vanilloid receptor 1 (TRPV1). This molecule is a heat-sensitive calcium/sodium ion channel and converts painful heat into nerve action potentials by depolarizing the pain sensing nerve terminals in the skin. Ion conductance is also stimulated by binding of capsaicin, a vanilloid compound and the active ingredient in hot pepper. This program has directly led to a bench to bedside application in which vanilloid agonists are used to kill pain-sensing neurons via ligand-induced calcium cytotoxicity and thereby provide pain control. The second program is centered on gene discovery in spinal cord. Subtraction cloning and differential hybridization has revealed new genes enriched in spinal cord and induced by pain stimuli. We are in the process of characterizing the known and novel genes. One gene has already been assessed due to its secretion into cerebrospinal fluid, in a human clinical protocol as a bio-marker for pain. Another is the receptor for neuropeptide FF which is known to be involved in opioid modulation of pain. This project is a long term, high-risk endeavor, which is setting new directions for molecular and clinical pain research. In addition to pain these studies fundamentally explore the molecular basis of synaptic plasticity in general, as we hypothesize a modularity in the neuronal response to a new level of synaptic or pharmacological input (e.g. learning, neurological disorders, drug abuse,). the translational studies are examining an ultrapotent vanilloid agonist, resiniferatoxin(RTX), as a pain control agent through removal of primary afferent pain sensing neurons. We developed an intraganglionic and intrathecal injection methods. The results demonstrate that RTX-induced pain cell deletion is a very effective approach to control of certain types of chronic pain especially those associated with cancer and arthritis.

我们的研究项目致力于中枢神经系统伤害性信息传递的基本分子和生理过程。分子研究是在动物和体外细胞模型中进行的。我们主要研究初级传入痛觉神经元及其在脊髓背侧的联系。脊髓背侧是伤害性信息处理的第一个突触连接部位，我们的研究发现它是持续性疼痛状态下神经元可塑性和基因表达改变的场所。我们的目的是从神经系统的“入门水平”来理解急性和慢性疼痛的分子和细胞生物学机制。通过克隆的热和化学反应离子通道在异种细胞系统中异地表达和在原代培养的背根神经节中自然表达，对物理疼痛刺激的转导的调节也在研究中。从这项基础研究中产生的控制伤害性信息传递的新方法在一项翻译研究计划中被提出。目前正在调查两个主要的基础科学问题。第一个中心是通过香草素受体1(TRPV1)传递疼痛的分子机制。这种分子是一种热敏的钙/钠离子通道，通过去极化皮肤中的痛觉神经末梢，将疼痛的热量转化为神经动作电位。辣椒素是一种香草类化合物，与辣椒中的活性成分结合也会刺激离子电导。这一计划直接导致了床边应用的试验台，其中香草类激动剂被用来通过配体诱导的钙细胞毒性来杀死痛觉神经元，从而提供疼痛控制。第二个项目的中心是脊髓中的基因发现。消减克隆和差异杂交揭示了在脊髓中丰富的、受疼痛刺激诱导的新基因。我们正在研究已知的和新的基因。一种基因已经被评估，因为它分泌到脑脊液中，在人类临床方案中作为疼痛的生物标记。另一个是神经肽Ff的受体，已知它参与了阿片类药物对疼痛的调节。这个项目是一项长期的、高风险的努力，它正在为分子和临床疼痛研究设定新的方向。除了疼痛，这些研究从根本上探索了突触可塑性的分子基础，因为我们假设神经元对新水平的突触或药物输入(例如学习、神经疾病、药物滥用等)的反应是模块化的。翻译研究正在研究一种超强的香草素激动剂，树脂毒素(RTX)，通过移除初级传入痛觉神经元来作为疼痛控制剂。我们开发了一种节内和鞘内注射的方法。结果表明，RTX诱导的疼痛细胞缺失是一种非常有效的方法来控制某些类型的慢性疼痛，特别是那些与癌症和关节炎相关的疼痛。