Neurogenic Amplification of Pancreatitis Pain

胰腺炎疼痛的神经源性放大

• 批准号: 8288067
• 负责人: KARIN N. WESTLUND-HIGH
• 金额: $ 44.98万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288067
• 关键词: Acetaldehyde; Acinar Cell; Action Potentials; Acute; Alcohol abuse; Alcohol-Induced Disorders; Alcohols; Analgesics; Animal Model; Arachidonic Acids; Behavior; Blood alcohol level measurement; Calcium; Cancerous; Cations; Cell membrane; Cells; Chronic; Chronic inflammatory pain; Clinical Treatment; Development; Diet; Dose; Ductal; Edema; Event; Exposure to; Fatty acid glycerol esters; Fibrosis; Future; Goals; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Injury; Ischemia; Knowledge; Lipids; Liquid substance; Malignant neoplasm of pancreas; Mediating; Methionine Enkephalin; Mission; Modeling; National Institute of Neurological Disorders and Stroke; Nerve; Nerve Endings; Neuropeptides; Neurosciences; Nociception; Opioid; Opioid Peptide; Organ; Outcome; Outcome Study; Oxygen; Pain; Pancreas; Pancreatitis; Patients; Peripheral; Proteins; Rattus; Research; Role; Signal Transduction; Stenosis; Study models; Testing; Tissues; United States National Institutes of Health; Vanilloid; Visceral Afferents; Visceral pain; afferent nerve; alcohol effect; alcohol exposure; alcohol induced pancreatic injury; base; cell type; central sensitization; chronic pain; chronic pancreatitis; endogenous opioids; gene therapy; improved; inflammatory pain; inhibitor/antagonist; lipid mediator; novel; overexpression; parent grant; pressure; receptor; research study; response; response to injury; stellate cell; visceral afferent nerve

DESCRIPTION (provided by applicant): For patients with inflamed or cancerous pancreas, the precipitating complaint is pain generated by local tissue inflammation, fibrosis, ductal stenosis, edema, and fluid pressure. The pain relayed by visceral afferent nerves from chronically inflamed pancreas can become severe and intractable with no effective long-term treatment options. The studies proposed in this competitive renewal extend the original aims of the parent grant with two serendipitously discovered novel and potentially related findings. Discovery #1: Our recent unpublished findings indicate that high fat diet and alcohol induce increased expression of transient receptor potential vanilloid 4 (TRPV4) channels on pancreas cells. TRPV4 channels are non-selective cation channels responsive to conditions present in the local cellular microenvironment after tissue injury, including lipid mediators and tissue edema. Some alcohol metabolites are lipid mediators that can activate TRPV4. Excessive TRPV4 activation initiates cellular influx of calcium that initiates damaging intracellular cascades and pancreas afferent nerve activation. Discovery #2: We found that pancreatic tissue damage, inflammation, and pain-related behaviors are significantly reduced by gene therapy inducing overexpression of the endogenous opioid peptide, met- enkephalin. We propose new studies using a chronic pancreatitis model in rats and clonal pancreatic cells to further investigate significant tissue injury-induced changes in the cell microenvironment that are relevant to inducible TRPV4 expression and activation responses during the development of chronic pain. Hypothesis: Alcohol-induced injury in pancreas cells increases TRPV4 expression and activation which are reduced by met-enkephalin protection Aim 1 Determine the effects of alcohol injury on TRPV4 expression and activation in the pancreas. Aim 2 Determine if alcohol-induced TRPV4 expression and activation is reduced by met-enkephalin. Our overall goal is to discover local cellular microenvironment interactions that impact chronic pain and that provide inroads for development of future clinical treatments for chronic inflammatory visceral pain. The impact of TRPV4 induced in local reactive cells after tissue damage and the role of TRPV4 in chronic pain have not been well studied. The findings will provide knowledge about analgesic, protective and reparative effects of met-enkephalin related to TRPV4. Expected outcomes of challenging pancreatic cells in vitro with TRPV4 activators are that TRPV4 expression and activation responses will increase, except in the presence of met- enkephalin. Further, TRPV4 inhibitors and met-enkephalin will reduce pain-related behaviors in the rat model of chronic pancreatitis. The findings will extend understanding of TRPV4 mediated events in the local microenvironment that impact both peripheral and central sensitization during the transition from acute to chronic visceral pain. Study of the transition to chronic pain is a mission of the NIH Blueprint and NINDS.

描述（由申请人提供）：对于胰腺发炎或癌变的患者，诱发的主诉是局部组织炎症、纤维化、导管狭窄、水肿和液体压力产生的疼痛。由于没有有效的长期治疗方案，慢性发炎的胰腺通过内脏传入神经传递的疼痛可能会变得严重且难以治愈。此次竞争性更新中提出的研究通过两个偶然发现的新颖且可能相关的发现扩展了家长资助的最初目标。发现#1：我们最近未发表的研究结果表明，高脂肪饮食和酒精会诱导胰腺细胞上瞬时受体电位香草酸 4 (TRPV4) 通道的表达增加。 TRPV4 通道是非选择性阳离子通道，对组织损伤后局部细胞微环境中存在的条件（包括脂质介质和组织水肿）做出响应。一些酒精代谢物是脂质介质，可以激活 TRPV4。过度的 TRPV4 激活会引发细胞钙内流，从而引发破坏性的细胞内级联反应和胰腺传入神经激活。发现#2：我们发现基因治疗诱导内源性阿片肽甲脑啡肽过度表达，可显着减少胰腺组织损伤、炎症和疼痛相关行为。我们提出了使用大鼠慢性胰腺炎模型和克隆胰腺细胞的新研究，以进一步研究组织损伤引起的细胞微环境的显着变化，这些变化与慢性疼痛发展过程中可诱导的 TRPV4 表达和激活反应相关。假设：酒精引起的胰腺细胞损伤会增加 TRPV4 表达和激活，而甲硫脑啡肽保护会减少 TRPV4 表达和激活 目的 1 确定酒精损伤对胰腺中 TRPV4 表达和激活的影响。目标 2 确定甲硫脑啡肽是否会降低酒精诱导的 TRPV4 表达和激活。我们的总体目标是发现影响慢性疼痛的局部细胞微环境相互作用，并为慢性炎症内脏疼痛的未来临床治疗的发展提供线索。组织损伤后TRPV4在局部反应细胞中诱导的影响以及TRPV4在慢性疼痛中的作用尚未得到充分研究。这些发现将提供有关 TRPV4 相关甲硫脑啡肽的镇痛、保护和修复作用的知识。用 TRPV4 激活剂在体外挑战胰腺细胞的预期结果是 TRPV4 表达和激活反应将会增加，除非存在甲脑啡肽。此外，TRPV4 抑制剂和甲硫脑啡肽将减少慢性胰腺炎大鼠模型中与疼痛相关的行为。这些发现将加深对TRPV4介导的局部微环境事件的理解，这些事件在从急性内脏疼痛转变为慢性内脏疼痛的过程中影响外周和中枢敏化。研究向慢性疼痛的转变是 NIH Blueprint 和 NINDS 的使命。