Neurogenic Amplification of Pancreatitis Pain

描述（由申请人提供）：对于胰腺炎症或癌变的患者，主要主诉是由局部组织炎症、纤维化、导管狭窄、水肿和液体压力引起的疼痛。胰腺慢性炎症的内脏传入神经传递的疼痛可能变得严重和难以处理，没有有效的长期治疗方案。在这种竞争性更新中提出的研究扩展了父母补助金的原始目标，其中有两个偶然发现的新颖和潜在相关的发现。发现#1：我们最近未发表的研究结果表明，高脂肪饮食和酒精诱导胰腺细胞瞬时受体电位香草样蛋白4 （TRPV4）通道的表达增加。TRPV4通道是一种非选择性阳离子通道，对组织损伤后局部细胞微环境的条件有反应，包括脂质介质和组织水肿。一些酒精代谢物是可以激活TRPV4的脂质介质。过度的TRPV4激活会引发钙的细胞内流，从而引发细胞内级联反应和胰腺传入神经激活。发现2：我们发现通过基因治疗诱导内源性阿片肽-脑啡肽的过度表达，胰腺组织损伤、炎症和疼痛相关行为显著减少。我们建议使用大鼠慢性胰腺炎模型和克隆胰腺细胞进行新的研究，以进一步研究组织损伤诱导的细胞微环境变化，这些变化与慢性疼痛发展过程中诱导的TRPV4表达和激活反应有关。假设：酒精诱导的胰腺细胞损伤增加TRPV4的表达和激活，而TRPV4的表达和激活被met-enkephalin保护而降低。目的2：确定乙醇诱导的TRPV4的表达和激活是否被脑啡肽降低。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，并为慢性炎症性内脏疼痛的未来临床治疗发展提供进展。组织损伤后TRPV4对局部反应细胞的影响以及TRPV4在慢性疼痛中的作用尚未得到很好的研究。该研究结果将提供有关脑啡肽与TRPV4相关的镇痛、保护和修复作用的知识。在体外用TRPV4激活剂刺激胰腺细胞的预期结果是，TRPV4的表达和激活反应将增加，但met-脑啡肽的存在除外。此外，TRPV4抑制剂和脑啡肽会减少慢性胰腺炎模型大鼠的疼痛相关行为。这一发现将扩大对TRPV4介导的局部微环境事件的理解，这些事件在从急性到慢性内脏疼痛的转变过程中影响外周和中枢致敏。研究过渡到慢性疼痛是NIH蓝图和NINDS的使命。

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 Discovery #1: Our recent unpublished findings indicate that high fat diet and alcohol induce increased expression of transient receptor potential vanilloid 4 (TRPV4) channels on pancreas cells.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.