Mechanisms of Probiotic Analgesia

说明(申请人提供)：目前的止痛药是有限的，因为副作用包括成瘾和器官损伤。事实上，NCCAM强调了对新型止痛药的需求是高度优先的。我们的长期目标是利用益生菌的潜力开发新的益生菌止痛药，用于治疗间质性膀胱炎/膀胱痛综合征(IC)的盆腔疼痛。我们以前研究了区分对尿路致病性大肠杆菌(UPEC)的症状反应与临床上与无症状菌尿(ASB)相关的大肠杆菌无反应的分子基础。我们现在已经积累了令人信服的初步数据，表明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。我们假设，以大肠杆菌为基础的益生菌的镇痛活性是通过作用于与膀胱疼痛信号有关的三个受体，Toll样受体4(TLR4)，瞬时的 受体势阳离子通道V亚家族成员1(TRPV1)和趋化因子C-C基序受体2(CCR2)。这些机制研究将确定益生菌大肠杆菌的止痛配体，并确定每个受体在IC小鼠模型中介导盆腔疼痛的作用。这些研究是高度创新的，我们不知道还有其他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止痛剂的新的机理理解，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。

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.