Neuromolecular Mechanisms of Chronic Pelvic Pain in Neonatally-induced Cystitis

新生儿膀胱炎慢性盆腔痛的神经分子机制

• 批准号: 9768433
• 负责人: BANANI B BANERJEE
• 金额: $ 63.52万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768433
• 关键词: Adult; Affect; Amygdaloid structure; Behavioral; Bladder; Brain; Brain Stem; Brain imaging; Brain region; Cell Nucleus; Characteristics; Child; Chronic; Clinic Visits; Clinical Research; Colon; Complex; Cystitis; Detection; Development; Electric Stimulation; Electrophysiology (science); Etiology; Event; Exposure to; Female; Funding; Genes; Genetic Transcription; Human; Hypersensitivity; Immunohistochemistry; In Situ Hybridization; Individual; Infant; Inflammation; Insula of Reil; Investigation; Ion Channel; Lead; Life; Mediating; Medical Care Costs; MicroRNAs; Midbrain structure; Modeling; Molecular; Molecular Profiling; Motor; Motor Cortex; National Institute of Diabetes and Digestive and Kidney Diseases; Neonatal; Neuronal Plasticity; Neurons; Nociception; Organ; Outcome; Outpatients; Pain; Pathway interactions; Patients; Pattern; Pelvic Pain; Pelvis; Pharmacology; Population; Preparation; Rattus; Regulation; Reporting; Saline; Seeds; Sensory; Signal Pathway; Small RNA; Spinal; Spinal Cord; Stimulus; Stress; Structure; Symptoms; Synapses; Synaptic Vesicles; Synaptosomes; Syndrome; System; Testing; Time; Tracer; United States National Institutes of Health; Untranslated RNA; Up-Regulation; Visceral; Western Blotting; Zymosan; base; bladder pain; central pain; chronic pain; chronic pelvic pain; colon distension; design; differential expression; experience; experimental study; functional MRI scan; imaging study; interest; mRNA sequencing; mad itch virus; miRNA expression profiling; midbrain central gray substance; neonatal period; neural circuit; neurophysiology; novel; pain perception; pain signal; preclinical study; receptor; response; sensory cortex; therapeutic target; urologic

SUMMARY There is a growing interest to understand how painful events in the neonatal period affect the development of nociceptive neural circuitry and alters pain perception in adulthood. Accumulating evidence from clinical studies indicates that the pain experience as a child has a significant impact on the pain responses at adulthood. Pre- clinical studies also clearly demonstrated that the exposure to noxious stimuli early in life causes long-term alterations in sensory processing. However, the etiology of chronic pelvic pain (CPP) is complex and poorly defined. The NIDDK has estimated that CPP is responsible for 4,137,000 outpatient or clinic visits/year and about 90% of them are female. Recent study also indicates that estimated medical cost for treating CPP exceeds $2 billion/year. The focus of our ongoing NIH application (R01 DK099201-01A1) is to study how the pain signaling pathway from the bladder to the spinal cord alters following neonatal bladder inflammation in rats. During this funding period, we have established for the first time the involvement of miRNAs (noncoding small RNAs) in post-transcriptional suppression of the developing spinal GABAergic system and long-term visceral hypersensitivity in a model of neonatal zymosan-induced cystitis. However, little is known regarding the involvement of supraspinal descending pain modulatory systems in spinal hyperexcitability following this early- life induced cystitis in rats. In this competitive renewal application, we would like to extend our study to investigate further the contribution of higher brain regions including midbrain PAG-RVM axis in the development of CPP in neonatal-cystitis rats. We will test the hypothesis that the long-lasting spinal sensitization following intense painful visceral stimulus in early-life is due to i) altered functional connectivity between PAG and higher brain regions ii) altered functional characteristics of RVM neurons projecting to spinal cord, and (iii) miRNA-mediated post-transcriptional dysregulation of pain modulatory neurons in the RVM. The proposed experiments will be systematic investigation to explore the intrinsic neuromolecular mechanisms and functional changes of descending pain modulation in neonatal cystitis-induced CPP. The identification of differentially expressed RVM miRNAs and molecular characterization of neuronal plasticity in the RVM neuron are of significance in designing receptor and/or miRNA-based pharmacological manipulation for better detection and therapeutic targeting of CPP.

概括 人们越来越有兴趣了解新生儿期的痛苦事件如何影响婴儿的发育。 伤害性神经回路并改变成年期的疼痛感知。从临床研究中积累证据 表明儿童时期的疼痛经历对成年后的疼痛反应有显着影响。预 临床研究也清楚地表明，生命早期接触有害刺激会导致长期的健康问题。 感觉处理的改变。然而，慢性盆腔疼痛（CPP）的病因复杂且缺乏有效的治疗方法。 定义的。 NIDDK 估计 CPP 每年负责 4,137,000 次门诊或诊所就诊， 其中约90%是女性。最近的研究还表明，治疗 CPP 的估计医疗费用超过 20 亿美元/年。我们正在进行的 NIH 申请 (R01 DK099201-01A1) 的重点是研究疼痛如何 大鼠新生膀胱炎症后从膀胱到脊髓的信号通路发生变化。 在此资助期间，我们首次确定了 miRNA（非编码小分子）的参与。 RNA）对发育中的脊髓 GABA 能系统和长期内脏系统的转录后抑制 新生儿酵母聚糖诱导的膀胱炎模型中的超敏反应。然而，人们对这方面知之甚少 在此早期，脊髓上下行疼痛调节系统参与脊髓过度兴奋 大鼠生命诱发的膀胱炎。 在这个竞争性的续订申请中，我们希望扩展我们的研究以进一步调查贡献 包括中脑 PAG-RVM 轴在内的高级脑区在新生膀胱炎大鼠 CPP 发展中的作用。 我们将检验以下假设：在剧烈疼痛的内脏刺激后，脊髓会出现持久的敏化。 早年生活是由于 i) PAG 和高级大脑区域之间的功能连接改变 ii) 功能改变 投射到脊髓的 RVM 神经元的特征，以及 (iii) miRNA 介导的转录后 RVM 中疼痛调节神经元的失调。拟议的实验将是系统的 研究探索下降性疼痛的内在神经分子机制和功能变化 新生儿膀胱炎诱导的 CPP 的调节。差异表达的 RVM miRNA 的鉴定和 RVM神经元神经元可塑性的分子表征对于设计受体具有重要意义 和/或基于 miRNA 的药理学操作，以更好地检测 CPP 和治疗靶向。