Integrative And Molecular Studies Of Pain & Pain Control

我们的研究项目涉及中枢神经系统伤害性传递的基本分子和生理过程。分子研究在动物和体外细胞模型中进行。我们集中研究脊髓背侧的初级传入痛觉神经元及其联系。背侧脊髓是伤害性信息处理的第一个突触连接部位，我们的研究已经确定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。我们的目的是了解神经系统中“入门级”急性和慢性疼痛的分子和细胞生物学机制。物理疼痛刺激的转导的调节也正在调查中使用克隆的热和化学反应离子通道异位表达在异源细胞系统和自然表达在背根神经节的原代培养物。新的方法来控制伤害性传递，从这个基础研究中出现的转化研究计划。目前正在研究两个主要的基础科学问题。第一个集中在疼痛通过香草素受体1（TRPV 1）转导的分子机制。这种分子是一种热敏钙/钠离子通道，通过使皮肤中的痛觉神经末梢去极化，将疼痛的热量转化为神经动作电位。离子电导也被辣椒素、一种香草素化合物和辣椒中的活性成分的结合所刺激。该计划直接导致了从实验室到床边的应用，其中香草素激动剂用于通过配体诱导的钙细胞毒性杀死疼痛感测神经元，从而提供疼痛控制。第二个项目集中在脊髓中的基因发现。差减克隆和差异杂交技术揭示了在脊髓中富集的疼痛刺激诱导的新基因。我们正在对已知的和新的基因进行鉴定。一个基因已经被评估，因为它分泌到脑脊液中，在人类临床协议中作为疼痛的生物标志物。另一个是神经肽FF的受体，已知其参与疼痛的阿片调节。该项目是一项长期、高风险的奋进，为分子和临床疼痛研究设定了新的方向。除了疼痛，这些研究从根本上探索一般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理学输入（例如学习，神经系统疾病，药物滥用）的反应具有模块性。翻译研究正在检查一种超强效的香草素激动剂，树脂毒素（RTX），作为通过去除初级传入痛觉神经元的痛觉控制剂。我们开发了神经节内和鞘内注射方法。结果表明，RTX诱导的疼痛细胞缺失是控制某些类型的慢性疼痛，特别是与癌症和关节炎相关的慢性疼痛的一种非常有效的方法。

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.