Neuoromolecular Mechanisms of Chronic Pelvic Pain in Neonatally-induced Cystitis

新生儿膀胱炎慢性盆腔疼痛的神经分子机制

• 批准号: 9058054
• 负责人: BANANI B BANERJEE
• 金额: $ 46.26万
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058054
• 关键词: ARHGEF5 gene; Absenteeism at work; Acids; Acute; Adult; Affect; Agonist; Animal Model; Bacterial Infections; Biological Markers; Bladder; Butyric Acids; Chronic; Clinic Visits; Clinical; Colitis; Colon; Complex; Cystitis; Development; Diagnosis; Disease; Down-Regulation; Early Diagnosis; Electrophysiology (science); Enzymes; Epidemiology; Etiology; Evaluation; Family; Fatigue; Female; Frequencies; Functional disorder; Gender; Gene Expression; Gene Targeting; Glutamates; Goals; Health; Health Expenditures; Heredity; Hindgut; Hyperalgesia; Infection; Inflammation; Injury; Interstitial Cystitis; Intervention; Intrathecal Injections; Investigation; Irritable Bowel Syndrome; Lead; Life; Measures; Mediating; Medical; Medical Care Costs; Mental Depression; Messenger RNA; MicroRNAs; Middle Insomnia; Modality; Molecular; Morphology; Motor; National Institute of Diabetes and Digestive and Kidney Diseases; Neonatal; Neural Pathways; Neurologic; Neurons; Neurotransmitter Receptor; Neurotransmitters; Nociception; Organ; Outcome; Outpatients; Pain; Pain management; Pathway interactions; Patients; Pelvic Pain; Pelvis; Physicians; Physiological; Play; Prevention strategy; Process; Productivity; Quality of life; Rattus; Recurrent pain; Reporting; Research; Risk Factors; Role; Saline; Signal Pathway; Site; Spinal; Spinal Cord; Stimulus; Stress; Structure; Symptoms; Synapses; Syndrome; System; Testing; Therapeutic Intervention; Time; Tissues; Ulcerative Colitis; United States; Untranslated RNA; Urinary tract infection; Uterine Fibroids; Visceral; Woman; Work; Zymosan; base; behavioral study; biomarker identification; bladder pain; chronic pain; chronic pelvic pain; clinical practice; cost; diagnostic biomarker; differential expression; disease phenotype; dorsal horn; emotional abuse; endometriosis; experience; functional disability; individual patient; inhibitor/antagonist; intense pain; intravesical; locked nucleic acid; men; neonate; neuroimaging; neurotransmission; novel diagnostics; novel therapeutics; overexpression; pain behavior; patient population; patient subsets; physical abuse; prostatitis; receptor; receptor expression; response; symporter; synaptic function; therapeutic target; time use; transmission process; treatment group; urologic; vesicular GABA transporter; zolpidem

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.

描述(申请人提供)：慢性盆腔疼痛(CPP)患者经历持续的疼痛和排尿的紧迫感(膀胱过度弯曲)导致生活质量下降。NIDDK计算出，CPP每年有413.7万人次的门诊或诊所就诊，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的病因很复杂，也很难理解。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(子宫肌瘤和子宫内膜异位症)和前列腺炎(前列腺炎)，通常与其他盆腔和周围的躯体结构重叠。早期尿路感染(UTI)是CPP的危险因素之一。强烈的疼痛刺激和膀胱炎 在新生儿期，可能会对神经发育产生不利影响，导致成年后出现CPP。由于早期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人完全不同，因此值得进一步研究。一项系统的研究将通过实施诊断生物标志物、有效的预防策略和治疗干预的发展而产生重大的临床影响。抑制性神经递质g-氨基丁酸(GABA)在痛觉调制中起重要作用，其功能缺失可促进慢性痛觉的发生。关于新生儿伤害性刺激对GABA能系统发育的影响，目前还知之甚少。由于早期生活发作而导致的长期疼痛状况可能会导致神经递质和受体表达的转录和/或翻译改变，从而导致成年后神经元功能、形态和突触连接的改变。虽然基因表达的这种变化如何导致慢性疼痛在很大程度上还不清楚，但最近的证据有力地表明，微小RNAs(miRNAs，小的非编码RNA)在细胞可塑性中发挥着重要作用。我们假设，在生命早期强烈痛苦的内脏刺激后的长期脊髓敏化涉及miRNA介导的转录后对新生儿发育中的GABA能途径的去调节。GABA能张力的丧失可能是由于(1)GABA合成不足(GABA合成酶GAD1和/或GAD2下调)，(2)GABAA受体亚单位下调(以及(3)脊髓K+，Cl-协同转运体2(KCC2)和囊泡GABA转运体(VGAT)下调)。这项拟议的研究是首次系统地研究成年后GABA能张力改变对CPP的内在神经分子机制的影响。