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Peripheral GABAA Receptor Signaling

外周 GABAA 受体信号传导

基本信息

批准号：
9013589
负责人：
MICHAEL S GOLD
金额：
$ 37.03万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9013589
关键词：
Accounting Affinity Agonist Attenuated Bicarbonates Biochemical Biological Cells Colon Crohn&apos s disease Data Disease Employee Strikes Endocrine Enteral Epithelial Cells Equilibrium GABA transporter Goals Health Hypersensitivity Inflammation Inflammatory Inflammatory Bowel Diseases Injury Intestines Intracolonic Irritable Bowel Syndrome Label Link Maintenance Mediating Modeling Molecular Mus Neuraxis Neurons Nociception Pain Pain Disorder Pain Threshold Pattern Peripheral Play Prevalence Process Receptor Activation Receptor Inhibition Receptor Signaling Regulation Rodent Role Series Signal Transduction Signaling Protein Source Spinal Techniques Testing Therapeutic Intervention Tissues Ulcerative Colitis Viral Vector Viscera Visceral Afferents Visceral pain Zymosan base behavioral study design effective therapy gamma-Aminobutyric Acid human tissue knock-down neurotransmission novel novel strategies novel therapeutic intervention overexpression patch clamp public health relevance receptor research study response single cell analysis synthetic enzyme

项目摘要

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.