Mechanisms of Probiotic Analgesia

益生菌镇痛机制

• 批准号: 8919246
• 负责人: David J Klumpp
• 金额: $ 39.57万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919246
• 关键词: Absence of pain sensation; Acute; Acute Pain; Adverse effects; Afferent Neurons; Affinity; Agonist; Analgesics; Attenuated; Bacteriuria; Bladder; CCL2 gene; CD14 Antigen; Capsaicin; Cations; Chronic; Clinical Data; Clinical Research; Clinical Trials; Data; Data Set; Development; Escherichia coli; Etiology; Genetic; Goals; Health; Inflammation; Interstitial Cystitis; Lidocaine; Life; Ligands; Lipopolysaccharides; Mediating; Medical; Medicine; Modeling; Molecular; Mus; Narcotics; National Center for Complementary and Alternative Medicine; Neurons; Non-Steroidal Anti-Inflammatory Agents; Organ; Pain; Pathogenesis; Pathway interactions; Patients; Pelvic Pain; Peripheral; Pharmacology; Probiotics; Protein Isoforms; Publishing; Relative (related person); Reporter; Role; Sensory; Signal Transduction; Spinal Ganglia; Staging; Structure; Symptoms; TRPV1 gene; Testing; Urinary tract infection; Uropathogenic E. coli; Virus Receptors; Work; addiction; allodynia; attenuation; base; beta-Chemokines; bladder pain; chronic pain; chronic pelvic pain; clinically relevant; innovation; intravesical; meetings; member; membrane flux; novel; pre-clinical; receptor; response; toll-like receptor 4

DESCRIPTION (provided by applicant): Current analgesics are limited due to adverse side effects including addiction and organ damage. Indeed, the need for novel analgesics is highlighted as a High Priority by NCCAM. Our long-term goal is to harness the potential of probiotics to develop new probiotic analgesics for treating pelvic pain of interstitial cystitis/bladder pain syndrome (IC). We previously examined the molecular basis that discriminates the symptomatic response to uropathogenic E. coli (UPEC) from the lack of response to E. coli clinically associated with asymptomatic bacteriuria (ASB). We have now accumulated compelling preliminary data demonstrating that E. coli-based probiotics alleviate both acute and chronic pelvic pain in clinically-relevant murine models that recapitulate key aspects of IC. We hypothesize that the analgesic activity of E. coli-based probiotics results from acting on three receptors involved in bladder pain signals, Toll- like receptor 4 (TLR4), transient receptor potential cation channel subfamily V member 1 (TRPV1), and chemokine C-C motif receptor 2 (CCR2). These mechanistic studies will define the analgesic ligands of probiotic E. coli and define the roles for each receptor in mediating pelvic pain in murine models of IC. These studies are highly innovative, and we are unaware of other groups studying analgesic probiotics for chronic pelvic pain. This project will thus result in a new mechanistic understanding of probiotic analgesics and provide critical pre-clinical data to drive these probiotics into clinical trials for IC.

描述（由申请人提供）：由于不良副作用（包括成瘾和器官损伤），目前的镇痛药有限。事实上，NCCAM强调了对新型镇痛药的需求，将其作为一个高度优先事项。我们的长期目标是利用益生菌的潜力开发新的益生菌镇痛剂，用于治疗间质性膀胱炎/膀胱疼痛综合征（IC）的骨盆疼痛。我们以前研究了区分尿路致病性大肠杆菌的症状反应的分子基础。coli（UPEC）对E.临床上与无症状菌尿（ASB）相关的大肠杆菌。我们现在已经积累了令人信服的初步数据表明，E。基于大肠杆菌的益生菌在临床相关的小鼠模型中缓解急性和慢性盆腔疼痛，这些模型概括了IC的关键方面。我们推测E.基于大肠杆菌的益生菌作用于参与膀胱疼痛信号的三种受体，Toll样受体4（TLR 4），瞬时 受体电位阳离子通道亚家族V成员1（TRPV 1）和趋化因子C-C基序受体2（CCR 2）。这些机制研究将确定益生菌E的镇痛配体。大肠杆菌，并确定每个受体在介导盆腔疼痛的小鼠模型IC的作用。这些研究是高度创新的，我们不知道其他研究小组正在研究止痛益生菌治疗慢性盆腔疼痛。因此，该项目将导致对益生菌镇痛剂的新的机制理解，并提供关键的临床前数据，以推动这些益生菌进入IC的临床试验。