Neuromolecular Mechanisms of Chronic Pelvic Pain in Neonatally-induced Cystitis

总结 人们越来越感兴趣的是了解新生儿期的疼痛事件如何影响新生儿的发育。 伤害性神经回路和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著影响。预处理 临床研究也清楚地表明，在生命早期暴露于有害刺激会导致长期的 感觉处理的改变然而，慢性盆腔痛（CPP）的病因复杂， 定义了NIDDK估计，CPP每年负责4，137，000次门诊或诊所就诊， 其中约90%为女性。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（R 01 DK 099201 - 01 A1）的重点是研究疼痛是如何发生的。 新生大鼠膀胱炎症后，从膀胱到脊髓的信号通路发生改变。 在此资助期间，我们首次建立了miRNAs（非编码小分子）参与的研究。 RNA）在转录后抑制发育中的脊髓GABA能系统和长期内脏 新生儿酵母多糖诱导膀胱炎模型中超敏反应。然而，人们对它知之甚少。 脊髓过度兴奋中的脊髓上下行疼痛调节系统的参与， 大鼠生活诱发性膀胱炎。 在这个竞争性的续约申请中，我们希望扩展我们的研究，以进一步调查 包括中脑PAG-RVM轴在内的高级脑区在膀胱炎大鼠CPP发生中的作用。 我们将检验这一假设，即强烈的疼痛内脏刺激后， 早期生活是由于i）PAG和高级脑区域之间的功能连接改变ii）功能连接改变 RVM神经元投射到脊髓的特征，和（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 探讨下行痛的内在神经分子机制和功能变化 调节新生儿膀胱炎诱导的CPP。差异表达的RVM miRNAs的鉴定和 RVM神经元可塑性的分子特征对受体设计具有重要意义 和/或基于miRNA的药理学操作，用于更好地检测和治疗CPP靶向。

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.