Molecular Mechanisms of Pain in Chronic Pancreatitis

描述(申请人提供)：慢性胰腺炎仍然是一种常见且具有挑战性的临床综合征。它的主要特征是疼痛，尽管有许多经验性的治疗方法，但一直难以有效治疗。十多年来，我们实验室一直在积极探索胰腺炎疼痛的分子发病机制。在这个过程中，我们建立了非常有用和相关的CP啮齿动物模型，并对特定分子，特别是电压依赖(Kv)和TRPV1离子通道以及神经生长因子(NGF)的贡献获得了有价值的见解。然而，很明显，我们需要学习的东西还有很多。在这项提议中，我们将重点放在先前所描述的转化生长因子β的作用上。在慢性炎症性疼痛的发病机制中的作用。虽然转化生长因子？在炎症反应中占有突出地位，但其参与伤害性致敏作用却鲜有人关注。我们的假设是转化生长因子？是感觉神经元功能的重要调节因子，通过胰腺特异性感觉神经元兴奋性和离子通道功能的改变，在慢性胰腺炎疼痛的发病机制中发挥重要作用。在这项提案中，我们将试图通过以下具体目的，使用包括分子、电生理和行为分析在内的综合多学科方法来证明这一假说：(1)确定转化生长因子的作用？体外对感觉神经元兴奋性和离子通道活性的影响(2)确定外源性转化生长因子？对疼痛行为和胰腺感觉神经元可塑性的影响(在体)(3)确定内源性转化生长因子的作用？慢性胰腺炎疼痛行为和感觉神经元可塑性的发病机制。这项提议的意义是双重的。首先，这将有助于更好地了解慢性胰腺炎疼痛的发病机制。其次，它将建立一个重要的新的生物学作用的转化生长因子？，打开了它参与许多其他慢性疼痛疾病，可能是炎症性或肿瘤性起源的可能性。

DESCRIPTION (provided by applicant): 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. 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, particularly voltage dependent (Kv) and TRPV1 ion channels and nerve growth factor, NGF. However, it is clear that there is much more that we need to learn. In this proposal, we will focus on a previously under scribed role of transforming growth factor beta, (TGF?) in the pathogenesis of chronic inflammatory pain. Although TGF? is prominent in the inflammatory mileu, its participation in nociceptive sensitization has received little attention. Our hypothesis is that TGF? is an important modulator of sensory neuronal function and plays a major role in the pathogenesis of pain in chronic pancreatitis via changes in pancreas-specific sensory neuronal excitability and ion channel function. In this proposal, we will attempt to prove this hypothesis, using a comprehensive multidisciplinary approach encompassing molecular, electrophysiological and behavioral assays, via the following specific aims: (1) To determine the effects of TGF? on sensory neuronal excitability and ion channel activity in vitro (2) To determine the effects of exogenous TGF? on pain behavior and pancreatic sensory neuronal plasticity (in vivo) (3)To determine the role of endogenous TGF? in the pathogenesis of pain behavior and sensory neuronal plasticity in chronic pancreatitis. The significance of this proposal is two-fold. First, it will provide a better understanding of the pathogenesis of pain in chronic pancreatitis. Secondly, it will establish a major new biological role for TGF?, opening up the possibility of its involvement in many other chronic painful disorders that may be inflammatory or neoplastic in origin.