Neuromolecular Mechanisms of Chronic Pelvic Pain in Neonatally-induced Cystitis

摘要 人们越来越有兴趣了解新生儿期的痛苦事件如何影响儿童的发育。 伤害性神经回路和改变成年后的痛觉。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重大影响。Pre- 临床研究也清楚地表明，在生命早期接触有害刺激会导致长期的 感觉处理的改变。然而，慢性盆腔疼痛(Cpp)的病因复杂而复杂。 已定义。NIDDK估计，CPP每年有4,137,000人次的门诊或诊所就诊， 其中约90%是女性。最近的研究还表明，治疗慢性阻塞性肺病的估计医疗费用超过 20亿美元/年。我们正在进行的NIH应用程序(R01 DK099201-01A1)的重点是研究疼痛是如何 新生大鼠膀胱炎后从膀胱到脊髓的信号通路改变。 在这一资助期间，我们首次确定了miRNAs(非编码小分子 转录后抑制发育中的脊髓GABA能系统和长期内脏 酵母多糖诱导的新生儿膀胱炎模型中的超敏反应。然而，人们对此知之甚少 脊椎上下行痛觉调制系统参与了早期脊髓过度兴奋性。 生命诱导性大鼠膀胱炎。 在这项竞争性续期申请中，我们希望延长我们的研究，以进一步调查其贡献 包括中脑PAG-RVM轴在内的高级脑区在新生膀胱炎大鼠慢性前列腺炎的发生发展中起重要作用。 我们将测试这一假设，即强烈痛苦的内脏刺激后的长期脊髓敏感化 早期生命的原因是：1)PAG和高级脑区之间的功能连接改变；2)功能改变 投射到脊髓的RVM神经元的特征和(III)miRNA介导的转录后 RVM中痛觉调制神经元的调节失调。拟议的实验将是系统化的。 下行疼痛的内在神经分子机制及功能改变的研究 新生儿膀胱炎所致慢性盆腔炎的调控。差异表达的RVM miRNAs和RVM miRNAs的鉴定 RVM神经元可塑性的分子表征对受体的设计具有重要意义 和/或基于miRNA的药理操作，以更好地检测和治疗CPP。

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.