Spinal Mechanisms Underlying SCI-Induced Pain: Implications for Targeted Therapy

SCI 引起的疼痛的脊柱机制：对靶向治疗的影响

• 批准号: 8312774
• 负责人: SUSAN G DORSEY
• 金额: $ 71.68万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-21 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312774
• 关键词: Address; Affect; American; Americas; Animal Model; Animals; Antibodies; Astrocytes; Behavior; Bilateral; Binding; Biological Assay; Brain-Derived Neurotrophic Factor; Cell Cycle; Cell Surface Receptors; Cells; Chronic; Cognitive deficits; Contusions; Cyclin-Dependent Kinases; Cyclins; Data; Development; Diabetes Mellitus; Diffuse; Drug Delivery Systems; Early treatment; Effectiveness; Enterobacteria phage P1 Cre recombinase; Epidemic; Epitopes; Event; Functional disorder; Genes; Genetic; Glial Fibrillary Acidic Protein; Growth Factor Receptors; Healthcare; Heart Diseases; Hour; Hyperalgesia; ITGAM gene; In Vitro; Injury; Institute of Medicine (U.S.); Intervention; Knock-in Mouse; Knockout Mice; Length; Location; Malignant Neoplasms; Mediating; Medicine; Messenger RNA; Microarray Analysis; Microglia; Modeling; Molecular Target; Motor; Mus; Neuronal Plasticity; Neurons; Neuropathy; Neurotrophic Tyrosine Kinase Receptor Type 2; Nociception; Pain; Pathway interactions; Patients; Peptides; Phosphotransferases; Population; Process; Productivity; Protein Isoforms; Public Health; RNA Splicing; Recovery; Recovery of Function; Regulation; Reporting; Research; Resistance; Role; Seminal; Sensory; Signal Transduction; Simulate; Spinal; Spinal Cord; Spinal Cord Plasticity; Spinal Injuries; Spinal cord injured survivor; Spinal cord injury; Spinal cord injury patients; Stimulus; Symptoms; Testing; Thermal Hyperalgesias; Time; Tissue-Specific Gene Expression; Transgenic Mice; Traumatic Brain Injury; Tropomyosin; Up-Regulation; Western Blotting; Work; allodynia; c-myc Genes; cdc Genes; cell type; central sensitization; chronic pain; conventional therapy; cost; dorsal horn; drug development; experience; flavopiridol; improved; improved functioning; in vivo; inhibitor/antagonist; mechanical allodynia; mouse model; nestin protein; neuroinflammation; neuron apoptosis; neuronal excitability; new therapeutic target; novel; novel therapeutic intervention; pain receptor; pre-clinical; promoter; receptor; receptor function; response; response to injury; roscovitine; spinal cord injury pain; spontaneous pain; therapeutic target

DESCRIPTION (provided by applicant): Chronic pain is a public health epidemic in the U.S., affecting more than 116 million people and costing greater than $600 billion per year to treat. Spinal cord injury (SCI) results not only in debilitating motor, sensory and cognitive deficits, bu also in a chronic, severe and often unrelenting pain that is largely resistant to conventional treatments (SCI-PAIN). Occurring in as many as 85% of SCI patients, pain starts weeks or months after the original insult, and includes increased pain with noxious stimulation (hyperalgesia), pain in response to previously innocuous stimuli (allodynia), and spontaneous pain. This unremitting pain can be diffuse, bilateral, and usually extends to locations caudal to the spinal injury. The delayed expression of SCI- PAIN and the diffuse localization of painful symptoms suggest that the pathophysiology reflects more than the direct effects at the denervated spinal segments. Indeed, these features of SCI-PAIN strongly suggest the occurrence of maladaptive plasticity in the spinal dorsal horn. An important focus for drug development has been to identify new therapeutic targets/molecules that participate in the spinal cord plasticity associated with the persistence of SCI-PAIN. One promising new therapeutic target, Brain-derived Neurotrophic Factor (BDNF), modulates nociception in the spinal cord. BDNF exerts its effects on nociceptive processing by binding to its full-length, cell surface receptor tropomyosin-related kinase B (trkB.FL) and initiating intracellular signaling. In addition to trkB.FL, the trkB locus also produces a widely-expressed alternatively-spliced truncated isoform, trkB.T1, but the function of this receptor isoform in nociception is largely unknown. TrkB.T1 is upregulated in several non-pain and pain related pathological states and we have reported that the genetic deletion of this receptor in mouse provides significant protection from the development of thermal hyperalgesia and mechanical allodynia across several models of chronic pain. Crucial to this proposal, we have preliminary data showing that trkB.T1 deletion results in significantly improved locomoter recovery and reduced allodynia in a moderate contusion injury mouse model of SCI developed by our group. We conducted differential gene expression studies to examine the potential transcriptional mechanisms regulating these improvements, and found that upregulation of key cell cycle genes correlating with neuronal apoptosis after experimental SCI, are not upregulated in the trkB.T1 null spinal cord. These results suggest that trkB.T1 may be an exciting new molecular target. In this study, we will systematically evaluate, using in vitro and in vivo approaches, whether trkB.T1 regulation of cell cycle genes contributes to SCI-PAIN and determine whether targeting cell cycle genes or trkB.T1, separately or in combination for enhanced effectiveness, can be utilized to develop novel therapeutic interventions to reduce or ameliorate SCI-PAIN. PUBLIC HEALTH RELEVANCE: Spinal cord injury causes a devastating loss of motor function. In addition, the majority of patients suffering from spinal cord injury experience chronic, unremitting shooting and stabbing pain that does not go away after taking pain medicines. We have identified potential new therapeutic targets, including a receptor for growth factors. In animals lacking this receptor, pain and motor function are improved. In this study, we will evaluate whether this new target could be used for drug development aimed at reducing or eliminating spinal cord injury pain.

描述(申请人提供)：慢性疼痛是美国的一种公共卫生流行病，影响着1.16亿人，每年的治疗费用超过6000亿美元。脊髓损伤(SCI)不仅导致衰弱的运动、感觉和认知障碍，而且还会导致对常规治疗(SCI-疼痛)基本抵抗的慢性、严重且往往是持续的疼痛。在多达85%的脊髓损伤患者中，疼痛在最初的伤害后几周或几个月开始，包括因伤害性刺激而增加的疼痛(痛觉过敏)，对先前无害的刺激产生的疼痛(痛觉异常)，以及自发疼痛。这种持续的疼痛可以是弥漫性的，双侧的，通常延伸到脊柱损伤的尾部。脊髓疼痛的延迟表达和疼痛症状的弥漫性定位表明，病理生理学反映的不仅仅是对失神经脊椎节段的直接影响。事实上，脊髓损伤疼痛的这些特征强烈表明脊髓背角发生了适应性不良的可塑性。药物开发的一个重要焦点是确定新的治疗靶点/分子，这些靶点/分子参与与脊髓持续疼痛相关的脊髓可塑性。一个有希望的新治疗靶点，脑源性神经营养因子(BDNF)，调节脊髓的伤害性感受。BDNF通过与其全长的细胞表面受体原肌球蛋白相关激酶B(trkB.FL)结合，启动细胞内信号传导，从而影响伤害性反应。除trkB.FL外，TrkB基因座还产生一种广泛表达的选择性剪接截断亚型trkB.T1，但该受体亚型在伤害性感受中的作用尚不清楚。TrkB.T1在几种非疼痛和疼痛相关的病理状态下表达上调，我们已经报道，在小鼠中，该受体的基因缺失在几种慢性疼痛模型中对热痛敏和机械性超敏的发展提供了显著的保护。对这一建议至关重要的是，我们有初步数据表明，trkB.T1缺失导致显著改善运动恢复，并减少我们团队建立的中度挫伤损伤小鼠脊髓损伤模型中的异位痛觉。我们进行了差异基因表达研究，以检验调控这些改进的潜在转录机制，并发现实验性脊髓损伤后与神经元凋亡相关的关键细胞周期基因上调，在trkB.T1缺失的脊髓中没有上调。这些结果表明trkB.T1可能是一个令人兴奋的新分子靶点。在这项研究中，我们将使用体外和体内的方法，系统地评估细胞周期基因trkB.T1的调节是否有助于SCI疼痛，并确定靶向细胞周期基因或trkB.T1是否可以单独或联合用于提高有效性，以开发新的治疗干预措施来减少或改善SCI疼痛。 公共卫生相关性：脊髓损伤会导致严重的运动功能丧失。此外，大多数脊髓损伤患者服用止痛药后，都会经历慢性、持续的射击和刺痛，这种疼痛不会消失。我们已经确定了潜在的新治疗靶点，包括生长因子受体。在缺乏这种受体的动物中，疼痛和运动功能得到改善。在这项研究中，我们将评估这个新靶点是否可以用于旨在减少或消除脊髓损伤疼痛的药物开发。