Neuoromolecular Mechanisms of Chronic Pelvic Pain in Neonatally-induced Cystitis

描述（由申请人提供）：慢性盆腔疼痛（CPP）患者经历持续疼痛和排尿紧迫感（膀胱反射亢进），导致生活质量差。据NIDDK计算，CPP每年负责4 137 000次门诊或诊所就诊，其中约90%是女性。最近的研究表明，治疗CPP的估计医疗费用超过20亿美元/年。CPP的病因复杂且难以理解。疼痛是由于任何盆腔结构的功能障碍和/或炎症引起的，包括膀胱（膀胱炎）、后肠（结肠炎、肠易激综合征）、子宫（纤维瘤和子宫内膜异位症）和前列腺（前列腺炎），通常与其他盆腔和周围躯体结构重叠。CPP的危险因素之一是早期尿路感染（UTI）。强烈的疼痛刺激和膀胱炎症 在新生儿期的CPP可能会对神经发育产生不利影响，导致成年期的CPP。由于早期生活炎症的潜在病理生理学可能与未经历任何早期生活事件的成年人完全不同，因此需要进一步研究。通过实施诊断性生物标志物、有效的预防策略和开发治疗性干预措施，系统性研究将产生重大的临床影响。 抑制性神经递质γ-氨基丁酸（GABA）在疼痛调制中起着关键作用，其功能的缺乏会促进慢性疼痛。新生儿伤害性刺激对GABA能系统发育的影响目前尚不清楚。由于早期生活事件引起的长期疼痛状况可能导致神经递质和受体表达的转录和/或翻译改变，从而导致成年期神经元功能、形态和突触连接的改变。虽然基因表达的这种变化如何诱导慢性疼痛在很大程度上是未知的，但最近的证据强烈表明微RNA（miRNAs，小的非编码RNA）在细胞可塑性中的重要作用。 我们推测，在生命早期强烈疼痛内脏刺激后的持久脊髓敏化涉及miRNA介导的新生儿GABA能通路的转录后失调。GABA能张力的丧失可能是由于（1）缺乏GABA合成（GABA合成酶gad 1和/或gad 2下调），（2）GABAA受体亚单位下调（和（3）脊髓中K+，Cl-共转运蛋白2（KCC 2）和囊泡GABA转运蛋白（VGAT）下调。 这项研究首次系统地研究了成年期GABA能紧张性改变导致CPP的内在神经分子机制。

DESCRIPTION (provided by applicant): The patients with chronic pelvic pain (CPP) experience unrelenting pain and urgency for voiding (hypereflexsive bladder) leading to poor quality of life. The NIDDK has calculated that CPP is responsible for 4,137,000 outpatient or clinic visits/year and about 90% of them are female. Recent study indicates that estimated medical cost for treating CPP exceeds $2 billion/year. The etiology of CPP is complex and difficult to understand. The pain arises due to dysfunction and/or inflammation of any of the pelvic structures including the urinary bladder (cystitis), hindgut (colitis, irritable bowel syndrome), uterus (fibroid and endometriosis) and prostrates (prostatitis) often overlaps to other pelvic and surrounding somatic structures. One of the risk factors for CPP is early episode of urinary tract infection (UTI). The intense painful stimulus and inflammation of the urinary bladder in the neonatal period may adversely affect the neurological development leading to CPP in adulthood. The underlying pathophysiology due to early-life inflammation could be entirely different from that of adults not subjected to any early-life episode and thus warrants further investigation. A systematic study will have significant clinical impact by implementing diagnostic biomarkers, effective prevention strategies and the development of therapeutic intervention. The inhibitory neurotransmitter g-amino butyric acid (GABA) plays a critical role in the pain modulation and lack of its function facilitates chronic pain. Very little is known about how the development of GABAergic system is affected due to neonatal noxious stimulus. A long- lasting pain condition due to early-life episodes may result in transcriptional and/or translational alteration in neurotransmitters and receptor expressions resulting altered neuronal functions, morphology and synaptic connections in adulthood. Although it is largely unknown how such changes in gene expressions induce chronic pain, recent evidence strongly suggests an important role for micro RNAs (miRNAs, small non-coding RNAs) in the cellular plasticity. We hypothesize that the long-lasting spinal sensitization following intense painful visceral stimulus in early-life involves miRNA-mediated posttranscriptional deregulation of developing GABAergic pathway in neonates. The loss of GABAergic tone could be due to (1) lack of GABA synthesis (downregulation of GABA synthesizing enzymes gad1 and/or gad2), (2) downregulation of GABAA receptor subunits (and (3) downregulation of K+, Cl- co- transporter 2 (KCC2) and vesicular GABA transporter (VGAT) in the spinal cord. The proposed study is the first systematic investigation of intrinsic neuromolecular mechanism involved in altered GABAergic tone contributing to CPP in adulthood.