Peripheral GABAA Receptor Signaling

 描述（由申请人提供）对于与炎性肠病（例如溃疡性结肠炎）或功能性肠病（例如肠易激综合征）相关的内脏疼痛，即使有持续有效的治疗，也是很少的。考虑到这些疾病的普遍性以及疼痛是患者的主要主诉这一事实，确定治疗内脏疼痛的新方法是非常重要的。中枢神经系统一直是疼痛背景下GABA信号改变的焦点。即使对于从外周传递“疼痛”信号所必需的初级传入神经，焦点也一直集中在中枢末梢的GABA调节上。事实上，我们和其他人已经描述了伤害性传入神经中枢末端的一些变化，导致GABAA受体（GAR）信号从抑制到兴奋的转变，使GABA能够促进炎症的疼痛和超敏反应。但如果伤害性传入外周末端的GAR信号也有助于伤害性信号的调节呢？毕竟，加尔斯也被运输到伤害性传入的外周末梢。在结肠中，GABA能肠神经元、上皮细胞和内分泌细胞是GABA的潜在来源。初步数据表明，在没有组织损伤的情况下，结肠内释放的内源性GABA可减弱结肠传入神经的兴奋性。引人注目的是，在炎性结肠超敏反应（即IBD样）模型中，结肠传入神经的外周GAR抑制作用丧失，并且出现了结肠传入神经的GAR依赖性兴奋非炎性（即IBS样）持续性结肠超敏反应。GAR信号的这些变化与IBD样模型中GABA合成酶的减少和IBS样模型中GABA调节机制的增加有关。因此，我们假设外周GAR信号传导的不同模式的变化有助于在炎性和非炎性内脏疼痛疾病中观察到的结肠超敏反应。以下三个具体目标描述了设计用于测试该假设以及鉴定GAR信号传导变化的潜在机制的实验。首先，我们建议在小鼠结肠组织损伤的情况下，确定GAR介导的传入活动抑制的机制。其次，我们将确定炎症和非炎症结肠过敏模型中GAR介导的结肠传入抑制的变化机制。第三，我们将在GAR信号机制的变化和结肠过敏之间建立因果关系。拟议的研究有可能改变GAR信号的当前观点，包括传入兴奋性的外周控制。更重要的是，它们可能为内脏疼痛的管理提出新的方法。

 DESCRIPTION (provided by applicant) There are few if any consistently effective treatments for the visceral pain associated with inflammatory bowel diseases such as ulcerative colitis, or functional bowel disorders such as Irritable Bowel Syndrome. Given the prevalence of these disorders and the fact that pain is a primary complaint of those who suffer, identification of nove approaches for the treatment of visceral pain is highly significant. The focus central nervous system has been the focus of altered GABA signaling in the context of pain. Even for the primary afferents essential for transmitting the "pain" signal from the periphery, the focus has been on GABA regulation of central terminals. Indeed, we and others have described a number of changes in the central terminals of nociceptive afferents resulting in a shift in GABAA-receptor (GAR) signaling from inhibition to excitation, enabling GABA to contribute to the pain and hypersensitivity of inflammation. But what if GAR signaling at the peripheral terminals of nociceptive afferents also contributes to the regulation of nociceptive signaling? After all, GARs are also transported to the peripheral terminals of nociceptive afferents. In the colon, GABAergic enteric neurons, epithelial cells and endocrine cells are potential sources of GABA. Preliminary data indicate that in the absence of tissue injury, endogenous GABA released within the colon serves to attenuate the excitability of colonic afferents. Strikingly, there is a loss of periphera GAR inhibition of colonic afferents in a model of inflammatory colonic hypersensitivity (i.e. IBD-like) and the emergence of GAR-dependent excitation of colonic afferents non-inflammatory (i.e. IBS-like) persistent colonic hypersensitivity. These changes in GAR signaling are associated with a decrease in GABA synthetic enzymes in the IBD-like model and increases in GABA regulatory machinery in the IBS-like model. Thus, we hypothesize that a distinct pattern of changes in peripheral GAR signaling contributes to the colonic hypersensitivity observed in inflammatory and non- inflammatory visceral pain disorders. Experiments designed to test this hypothesis as well as identify mechanisms underlying the changes in GAR signaling are described under the following three Specific Aims. First, we propose to determine mechanisms underlying GAR-mediated suppression of afferent activity in the absence of tissue injury in the mouse colon. Second, we will determine the mechanisms underlying the changes GAR-mediated inhibition of colonic afferents in models of inflammatory and non-inflammatory colonic hypersensitivity. Third, we will establish a causal link between changes in GAR signaling mechanisms and colonic hypersensitivity. The proposed studies have the potential to transform the current view of GAR signaling to include the peripheral control of afferent excitability. More importantly, they may suggest novel approaches for the management of visceral pain.