Integrative And Molecular Studies Of Pain & Pain Control

我们的研究项目涉及中枢神经系统中伤害性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。我们集中在初级传入痛觉神经元和他们的连接背脊髓。脊髓背侧是伤害性信息处理的突触连接的第一个部位，我们的研究已经确定它是持续疼痛状态下神经元可塑性和基因表达改变的位点。我们的目的是了解急性和慢性疼痛的分子和细胞生物学机制在神经系统的“入门级”。通过在异源细胞系统中异位表达和在背根神经节原代培养中自然表达的克隆热和化学反应离子通道，也在研究物理疼痛刺激的转导调节。从基础研究中出现的控制伤害性传播的新方法在转化研究计划中得到解决。目前正在研究两个主要的基础科学问题。第一个重点是通过香草样受体1 （TRPV1）进行疼痛转导的分子机制。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，将痛觉热量转化为神经动作电位。辣椒素是一种香草化合物，也是辣椒中的活性成分，它的结合也会刺激离子的传导。这个项目直接导致了从实验到临床的应用，香草受体激动剂通过配体诱导的钙细胞毒性杀死痛觉神经元，从而提供疼痛控制。第二个项目的重点是发现脊髓中的基因。减法克隆和差异杂交揭示了在脊髓中富集并受疼痛刺激诱导的新基因。我们正在描述已知的和新的基因。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志物。另一种是神经肽FF的受体，已知它参与阿片样物质对疼痛的调节。该项目是一项长期、高风险的努力，为分子和临床疼痛研究开辟了新的方向。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，神经系统疾病，药物滥用）的反应是模块化的。转化研究正在研究一种超强香草受体激动剂，树脂干扰素（RTX），作为一种通过去除初级传入痛觉神经元来控制疼痛的药物。我们发展了腱鞘内和鞘内注射方法。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，特别是与癌症和关节炎相关的慢性疼痛。

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.