Neonatal Bladder Inflammation, Opioids, and Adult Bladder Pain

新生儿膀胱炎症、阿片类药物和成人膀胱疼痛

• 批准号: 8011777
• 负责人: ALAN RANDICH
• 金额: $ 4.57万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-20 至 2011-01-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011777
• 关键词: Adolescent; Adult; Agonist; Animal Testing; Bacterial Infections; Bladder; Bladder Diseases; Bladder Tissue; Blood Pressure; Cells; Development; Disease; Electric Stimulation; Enzyme-Linked Immunosorbent Assay; Estrous Cycle; Exposure to; Female; Frequencies; Heating; Hour; Hyperalgesia; Hyperreflexia; Ibotenic Acid; Incidence; Increased frequency of micturition; Individual; Inflammation; Inflammatory; Interstitial Cystitis; Intervention; Knowledge; Lesion; Life; Life Experience; Methodological Studies; Microinjections; Micturition Reflex; Modality; Modeling; Naloxone; Neonatal; Neurons; Opioid; Opioid Peptide; Opioid Receptor; Organism; Outcome; Pain; Peripheral; Population; Posterior Horn Cells; Process; Rattus; Reflex action; Research; Spinal; Spinal Cord; Staging; Symptoms; System; Tail; Testing; Translations; Urinary tract; Urination; Western Blotting; Zymosan; base; early experience; endogenous opioids; experience; extracellular; human TFRC protein; innovation; neonatal exposure; novel therapeutics; painful bladder syndrome; programs; public health relevance; receptor; receptor expression; relating to nervous system; response

DESCRIPTION (provided by applicant): Our previous research in rats has shown that exposure to bladder inflammation during the neonatal period of development markedly enhances the degree of bladder hyperalgesia that occurs in response to a second exposure to bladder inflammation as an adult. Neonatal bladder inflammation also significantly increases micturition frequency and significantly decreases the threshold for micturition reflexes in adulthood. These outcomes are consistent with the primary symptoms of painful bladder syndrome (PBS) / interstitial cystitis (IC) and suggest that neonatal bladder inflammation may be a contributing factor to bladder disorders. The general hypothesis of the present proposal is that neonatal bladder inflammation predisposes an organism to adult bladder pain by impairing the development and/or function of an opioid inhibitory system that normally serves to suppress bladder pain. The specific hypotheses that refine and develop this general hypothesis are tested in the following specific aims: Specific Aim 1 will test the hypothesis that the estrous cycle influences the magnitude of the endogenous opioid inhibitory response evoked by bladder inflammation in the adult rat. Specific Aim 2 will test the hypothesis that neonatal bladder inflammation predisposes an organism to adult bladder pain by impairing a descending inhibitory system originating from neurons located in the rostroventral medulla (RVM). Specific Aim 3 will test the hypothesis that neonatal bladder inflammation predisposes an organism to adult bladder pain by altering <-, :- and/or 4-opioid receptor expression in the spinal cord. Specific Aim 4 will test the hypothesis that neonatal bladder inflammation predisposes an organism to adult bladder pain by altering spinal cord opioid peptide content. Specific Aim 5 will test the hypothesis that neonatal bladder inflammation predisposes an organism to adult bladder pain by reducing opioid inhibition of spinal dorsal horn neurons We believe these systematic studies, based on an innovative hypothesis, will lay the groundwork for potential novel therapeutic modalities for the treatment of urinary bladder pain by identifying opposing substrates underlying the development of bladder pain. Translation to the treatment of painful bladder syndromes would be highly probable because we will be able to identify key loci for targeted interventions. PUBLIC HEALTH RELEVANCE: We believe these systematic studies, based on an innovative hypothesis, will lay the groundwork for potential novel therapeutic modalities for the treatment of urinary bladder pain associated with painful bladder syndrome (PBS) / interstitial cystitis (IC) by identifying opposing substrates underlying the development of bladder pain. Translation to the treatment of PBS/IC would be highly probable because we will be able to identify key developmental factors that give rise to the disorders, underlying mechanisms responsible for the disorders, and loci for targeted interventions.

描述（由申请人提供）：我们之前在大鼠中的研究表明，在新生儿发育期间暴露于膀胱炎症显著增强了膀胱痛觉过敏的程度，该程度是对成年后第二次暴露于膀胱炎症的反应。新生儿膀胱炎症也会显著增加排尿频率，并显著降低成年期排尿反射的阈值。这些结果与膀胱疼痛综合征（PBS）/间质性膀胱炎（IC）的主要症状一致，表明新生儿膀胱炎症可能是膀胱疾病的一个促成因素。本提案的一般假设是，新生儿膀胱炎症通过损害通常用于抑制膀胱疼痛的阿片类药物抑制系统的发育和/或功能，使生物体更容易出现成人膀胱疼痛。在以下具体目标中，对完善和发展这一一般假设的具体假设进行了检验： 具体目标1将检验以下假设：动情周期影响成年大鼠膀胱炎症诱发的内源性阿片类药物抑制反应的幅度。具体目标2将检验以下假设：新生儿膀胱炎症通过损害起源于位于头腹侧髓质（RVM）的神经元的下行抑制系统，使生物体易于发生成人膀胱疼痛。具体目标3将检验以下假设：新生儿膀胱炎症通过改变脊髓中的α-、β-和/或4-阿片受体表达而使生物体易患成人膀胱疼痛。具体目标4将检验新生儿膀胱炎症通过改变脊髓阿片肽含量使生物体易患成人膀胱疼痛的假设。具体目标5将检验以下假设：新生儿膀胱炎症通过减少脊髓背角神经元的阿片样物质抑制而使生物体易于发生成人膀胱疼痛 我们相信，这些系统的研究，基于一个创新的假设，将奠定基础，为潜在的新的治疗方式，膀胱疼痛的治疗，通过确定膀胱疼痛的发展背后的对立基板。翻译为治疗疼痛性膀胱综合征将是非常有可能的，因为我们将能够确定有针对性的干预措施的关键位点。 公共卫生相关性：我们相信，这些系统的研究，基于一个创新的假设，将奠定基础的潜在的新的治疗方式，膀胱疼痛综合征（PBS）/间质性膀胱炎（IC）相关的膀胱疼痛的治疗，通过确定膀胱疼痛的发展背后的对立基板。转化为PBS/IC的治疗将是非常有可能的，因为我们将能够确定引起疾病的关键发育因素，负责疾病的潜在机制，以及靶向干预的位点。