Validation of peripheral CGRP signaling as a target for the treatment of pain in chronic pancreatitis

验证外周 CGRP 信号作为治疗慢性胰腺炎疼痛的靶标

• 批准号: 10764850
• 负责人: PANKAJ J PASRICHA
• 金额: $ 33.81万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-17 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10764850
• 关键词: Validation; peripheral; CGRP; signaling; target

Abstract Chronic pancreatitis remains a common and challenging clinical syndrome. Its cardinal feature, pain, has been difficult to treat effectively despite a multitude of empirical therapeutic approaches often leading to opioid addiction. Our laboratory has been actively pursuing the molecular pathogenesis of pain in pancreatitis for over a decade. In the process, we have established highly useful and relevant rodent models of CP and gained valuable insight into the contribution of specific molecules, such as nerve growth factor, NGF and transforming growth factor beta (TGF ). These molecules appear to be acting by a common effector and our preliminary data implicates calcitonin-gene related peptide (CGRP). CGRP has been classically thought to mediate pain by its role as a neurotransmitter relaying signals to second order neurons in the spinal cord (i.e. a central role) and in the case of migraine specifically, as a potent vasodilator. Recent developments in the treatment of migraine have increased interest in anti-CGRP strategies for pain. However, many questions about the mechanisms of action remain. Our overall hypothesis in this proposal is that peripheral CGRP is a major mediator of peripheral nociceptive sensitization in chronic pancreatitis and that peripherally restricted anti-CGRP treatment is an efficient and sufficient approach for pain in this condition. We will attempt to prove this hypothesis, using a comprehensive multidisciplinary approach encompassing molecular, electrophysiological and behavioral assays. The significance of this proposal is that if will validate CGRP as a therapeutic target, opening up the possibility for new non-addictive therapies in many other chronic painful disorders that may be inflammatory in origin.

摘要 慢性胰腺炎仍然是一种常见的和具有挑战性的临床综合征。它的主要特征，疼痛， 尽管许多经验性治疗方法经常导致阿片类药物， 成瘾我们的实验室一直在积极研究胰腺炎疼痛的分子发病机制， 超过十年。在此过程中，我们建立了非常有用和相关的啮齿动物CP模型， 获得了有价值的见解的贡献，具体的分子，如神经生长因子，神经生长因子和 转化生长因子β（TGF）。这些分子似乎是由一个共同的效应器和我们的 初步数据表明降钙素基因相关肽（CGRP）。CGRP被经典地认为 通过其作为神经递质将信号中继到脊髓中的二级神经元（即， 一个中心作用），并在偏头痛的情况下，特别是作为一个有效的血管扩张剂。最近的事态发展 偏头痛的治疗增加了对疼痛的抗CGRP策略的兴趣。然而，许多问题 关于作用机制的问题仍然存在。我们在这个建议中的总体假设是，外周CGRP是一种 慢性胰腺炎外周伤害性敏感化的主要介质和外周限制性 抗CGRP治疗对于这种情况下的疼痛是有效且充分的方法。我们将试图证明 这一假设，使用一个全面的多学科的方法，包括分子， 电生理和行为测定。该提案的意义在于，如果将验证CGRP作为 一个治疗目标，开辟了新的非成瘾性疗法在许多其他慢性疼痛的可能性， 可能是炎症性疾病。