Descending modulation of behavioral hyperalgesia after injury

损伤后行为痛觉过敏的降序调节

• 批准号: 7251546
• 负责人: RONALD DUBNER
• 金额: $ 32.48万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251546
• 关键词: AMPA Receptors; Agonist; Animal Model; Animals; Astrocytes; Behavior; Behavioral; Behavioral Model; Brain Stem; Brain-Derived Neurotrophic Factor; Chemicals; Cognitive; Condition; Couples; Data; Disease; Equilibrium; Excitatory Amino Acid Receptors; Fibromyalgia; Freund' s Adjuvant; Glutamate Receptor; Hyperalgesia; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-10; Irritable Bowel Syndrome; Isoxazoles; Lead; Link; Local Anesthetics; Location; Maintenance; Mediating; Mediator of activation protein; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Nerve Block; Neurons; Opioid; Pain; Pathway interactions; Persistent pain; Phase; Phosphorylation; Phosphotransferases; Play; Process; Propionic Acids; Propionic acid; Publishing; Receptor Activation; Research Personnel; Role; Sensory Thresholds; Serotonin; Serotonin Receptors 5-HT-3; Signal Transduction; Staining method; Stains; Stimulus; Substance P; Tachykinin Receptor; Temporomandibular Joint Disorders; Testing; Time; cytokine; human NR1 protein; inflammatory neuropathic pain; inhibitor/antagonist; kinase inhibitor; neuromechanism; neurotrophic factor; programs; protein expression; receptor; receptor expression; response; spinal pathway; src-Family Kinases; transmission process

DESCRIPTION (provided by applicant): Brain stem descending pathways constitute a major mechanism in the modulation of pain transmission by which attentional, motivational and cognitive variables filter ascending information. Recent studies indicate that hyperalgesia in animal models of persistent pain is linked to enhanced activation of descending inhibitory and facilitatory modulatory circuits. Such mechanisms may play an important role in persistent pain conditions such as fibromyalgia, temporomandibular joint disorders, and irritable bowel syndrome by increasing endogenous facilitation leading to an enhancement and spread of the pain. In earlier studies we focused mainly on the activity-dependent plasticity and dynamic temporal changes occurring in the rostral ventromedial medulla (RVM) within the first 24h after complete Freund's adjuvant (CFA)-induced inflammation. The cellular mechanisms mainly responsible for descending inhibition included excitatory amino acid receptors. Less is known about the effects of chemical mediators that contribute to the initiation and maintenance of descending facilitation and behavioral hyperalgesia after inflammation. Therefore, a major objective of our proposal is to determine the chemical signature of RVM circuits involved in the initiation and maintenance of descending facilitation of inflammatory hyperalgesia. Our major hypothesis is that inflammation leads to an increase in the release of multiple chemical mediators whose chemical signature involves activation of a signal transduction cascade in RVM neurons that couples their activity to subunits of the N-methyl-D-aspartate (NMDA) receptor and a descending serotoninergic pathway. We will test these hypotheses utilizing behavioral, molecular, immunohistochemical and pharmacological approaches in the aims presented below. Aim 1 will test the hypothesis that the balance between descending facilitation and inhibition and their contribution to inflammatory hyperalgesia is dependent, in part, upon the activation of multiple receptors for glutamate, proinflammatory cytokines, brain-derived neurotrophic factor (BDNF) and Substance P. Aim 2 will test the hypothesis that activation of the receptors for these chemical mediators in the RVM involves changes in receptor expression levels and their activation of signal transduction cascades that lead to phosphorylation of NMDA receptor subunits. Aim 3 will test the hypothesis that the time course of effect of these chemical mediators is differentially dependent upon primary afferent drive during the initiation and maintenance phases of behavioral hyperalgesia. Aim 4 will test the hypothesis that descending facilitation produced by BDNF, SP and proinflammatory cytokines is mediated through serotonin-containing descending pathways and spinal 5-HT3 receptors. Finally, Aim 5 will test the hypothesis that these chemical mediators in the RVM contribute to the aversive component of behavioral hyperalgesia via descending circuits originating in the RVM.

描述（由申请人提供）：大脑茎降途径构成了调节疼痛传播的主要机制，通过该机制，注意，动机和认知变量过滤升级信息。最近的研究表明，持续性疼痛的动物模型中的痛觉过敏与增强抑制性和促进调节回路的激活有关。这种机制在持续性疼痛状况中可能起重要作用，例如纤维肌痛，颞下颌关节疾病和肠易激综合征，通过增加内源性促进，从而增强和扩散疼痛。在较早的研究中，我们主要集中于依赖活性的可塑性和动态时间变化，在完整的Freund辅助（CFA）引起的炎症之后，在前24H内发生了腹侧胸腔髓质（RVM）。主要负责下降抑制的细胞机制包括兴奋性氨基酸受体。关于化学介质的效果，有助于促进和维持炎症后降低的促进和行为痛觉过敏的影响。因此，我们提案的一个主要目的是确定参与炎症性痛觉过敏的促进和维持涉及的RVM电路的化学特征。我们的主要假设是，炎症导致多个化学介质的释放增加，这些化学介质涉及在RVM神经元中激活信号转导级联反应，该cascade将其活性耦合到N-甲基-D-天冬氨酸（NMDA）受体的亚基和降低血清素能途径。我们将在下面提出的目的中利用行为，分子，免疫组织化学和药理学方法来检验这些假设。目标1将检验以下假设：下降促进和抑制之间的平衡及其对炎症性超痛觉过敏的贡献在某种程度上取决于多种受体的激活谷氨酸，促炎细胞因子，促进性细胞因子，脑源性的神经营养因子（BDNF）和物质P. AIM 2的受体对这些化学因素的转化，以使这些受体的变化涉及这些化学因素，这些受体会因这些化学的变化而进行了变化。表达水平及其激活信号转导级联导致NMDA受体亚基的磷酸化。 AIM 3将检验以下假设：这些化学介体的时间效果差异取决于行为痛觉过敏的启动和维持阶段中的主要传入驱动器。 AIM 4将检验以下假设：BDNF，SP和促炎细胞因子产生的下降促进性是通过含5-羟色胺的降途径和脊柱5-HT3受体介导的。最后，AIM 5将检验以下假设：RVM中的这些化学介质通过源自RVM的下降电路有助于行为痛觉过敏的厌恶成分。