Inflammatory hyperalgesia mediated by TRPV1, the pepper spray receptor in cornea

描述(申请人提供)：角膜中的化学和热痛主要由一种名为TRPV1的钙和钠渗透离子通道传递，TRPV1表达于三叉神经节胞体的伤害性感受器中。当受伤(包括手术)或疾病引起炎症时，炎症过程会增加TRPV1离子通道对疼痛刺激的敏感性，这种现象被称为炎症性痛觉过敏。我们的长期目标是了解介导炎性痛觉过敏的分子机制，这是开发更有效的角膜损伤疼痛疗法的关键第一步。在本研究中，我们将重点研究神经生长因子(NGF)对TRPV1调控的分子机制。炎症和损伤导致NGF、胰岛素和胰岛素样生长因子等营养因子的释放，这些营养因子通过激活受体酪氨酸激酶(RTK)增加伤害性感受器的兴奋性。已有研究表明，RTK的激活通过4，5-二磷酸肌醇(PIP2)的水解使TRPV1增敏，解除了PIP2对TRPV1的紧张性抑制。然而，PIP2的作用存在争议，因为越来越多的证据表明，3，4，5-三磷酸(PIPS)可能参与了PIP2的作用。根据我们的初步数据，我们认为PIP2被磷脂酰肌醇3-激酶(PI3K)磷酸化形成PIP3可能是NGF对伤害性感受器增敏的一个重要因素。我们的具体目标是探讨NGF调节TRPV1的分子机制和功能意义。了解RTK对TRPV1的调节对于全面了解炎症如何调节角膜伤害性感受器的兴奋性以及开发改进的治疗炎症性疼痛的方法至关重要。

DESCRIPTION (provided by applicant): Chemical and thermal pain in the cornea is primarily transduced by a calcium- and sodium-permeable ion channel called TRPV1 expressed in nociceptors with cell bodies in the trigeminal ganglia. When injury (including surgery) or illness cause inflammation, the inflammatory process increases the sensitivity of TRPV1 ion channels to painful stimuli, a phenomenon known as inflammatory hyperalgesia. Our long-term goal is to understand the molecular mechanisms mediating inflammatory hyperalgesia, a critical first step in developing more effective pain therapies for corneal injury. In this study, we will focus on the molecular mechanisms of TRPV1 modulation by Nerve Growth Factor (NGF). Inflammation and injury lead to release of trophic factors such as NGF, insulin, and Insulin-like Growth Factor, which increase nociceptor excitability by activating receptor tyrosine kinases (RTKs). It has been proposed that RTK activation sensitizes TRPV1 through hydrolysis of phosphoinositide 4,5-bisphosphate (PIP2), relieving a tonic inhibition of TRPV1 by PIP2. The role of PIP2 is controversial, however, due to emerging evidence that phosphoinositide 3,4,5- trisphosphate (PIPS) may be involved. Based on our preliminary data, we propose that phosphorylation of PIP2 by phosphoinositide 3-kinase (PI3K) to form PIP3 may be an essential element of nociceptor sensitization by NGF. Our specific aims will address the molecular mechanism and functional significance of TRPV1 modulation by NGF. Understanding the regulation of TRPV1 by RTKs is critical to a complete understanding of how inflammation modulates corneal nociceptor excitability and to the development of improved therapies to treat inflammatory pain.