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.

抽象的 慢性胰腺炎仍然是一种常见且具有挑战性的临床综合征。它的基本特征，疼痛 尽管经常导致阿片类药物，但很难有效治疗 瘾。我们的实验室一直在积极追求胰腺炎疼痛的分子发病机理 十多年。在此过程中，我们建立了CP的非常有用和相关的啮齿动物模型 对特定分子的贡献，例如神经生长因子，NGF和 转化生长因子β（TGF）。这些分子似乎是由共同效应器和我们的 初步数据暗示降钙素与基因相关的肽（CGRP）。 CGRP经过经典认为 通过作为神经递质传递信号到脊髓中的二阶神经元的神经递质的作用来介导疼痛（即 特别是偏头痛的中心作用，是有效的血管扩张剂。最近的发展 偏头痛的治疗增加了对抗CGRP疼痛策略的兴趣。但是，很多问题 关于作用机制仍然存在。我们在此提案中的总体假设是外围CGRP是一个 慢性胰腺炎中周围伤害感受敏化的主要介体和外周限制 在这种情况下，抗CGRP治疗是一种有效且足够的疼痛方法。我们将尝试证明 该假设使用综合的多学科方法，包括分子 电生理和行为测定。该提议的重要性是，如果将CGRP验证为 一个治疗靶标，为许多其他慢性痛苦中的新非添加疗法打开了可能性 可能起源的疾病。